Compounds and methods for the inhibition of the expression of VCAM-1

ABSTRACT

This invention is in the area of methods and compositions for the inhibition of the expression of VCAM-1 and, in particular, for the treatment of diseases mediated by VCAM-1, including cardiovascular and inflammatory diseases.

RELATIONSHIP TO PRIOR APPLICATIONS

This application is a continuation of U.S. Ser. No. 09/370,046 filed onAug. 6, 1999, now allowed, which is a continuation of U.S. Ser. No.09/079,213 filed on May 14, 1998, now U.S. Pat. No. 6,147,250, whichclaims priority to U.S. provisional application Ser. No. 60/047,020filed on May 14, 1997.

FIELD OF THE INVENTION

This invention is in the area of methods and compositions for inhibitingthe expression of VCAM-1 and, in particular, for the treatment ofdiseases mediated by VCAM-1, including cardiovascular and inflammatorydisease.

BACKGROUND OF THE INVENTION

Coronary heart disease (CHD) remains the leading cause of death in theindustrialized countries. The primary cause of CHD is atherosclerosis, adisease characterized by the deposition of lipids in the arterial vesselwall, resulting in a narrowing of the vessel passages and ultimatelyhardening the vascular system.

Atherosclerosis as manifested in its major clinical complication,ischemic heart disease, continues to be a major cause of death inindustrialized countries. It is now well accepted that atherosclerosiscan begin with local injury to the arterial endothelium followed byproliferation of arterial smooth muscle cells from the medial layer tothe intimal layer along the deposition of lipid and accumulation of foamcells in the lesion. As the atherosclerotic plaque develops itprogressively occludes more and more of the affected blood vessel andcan eventually lead to ischaemia or infarction. Therefore, it isdesirable to provide methods of inhibiting the progression ofatherosclerosis in patients in need thereof.

Cardiovascular disease has been linked to several causative factors,which include hypercholesterolemia, hyperlipidemia, and the expressionof VCAM-1 in vascular endothelial cells.

Expression of VCAM-1

Adhesion of leukocytes to the endothelium represents a fundamental,early event in a wide variety of inflammatory conditions, includingatherosclerosis, autoimmune disorders and bacterial and viralinfections. Leukocyte recruitment to the endothelium is started wheninducible adhesion molecule receptors on the surface of endothelialcells interact with counterreceptors on immune cells. Vascularendothelial cells determine which type of leukocytes (monocytes,lymphocytes, or neutrophils) are recruited, by selectively expressingspecific adhesion molecules, such as vascular cell adhesion molecule-1(VCAM-1), intracellular adhesion molecule-1 (ICAM-1), and E-selectin. Inthe earliest stage of the atherosclerotic lesion, there is localizedendothelial expression of VCAM-1 and selective recruitment ofmononuclear leukocytes that express the integrin counterrecptor VLA-4.Because of the selective expression of VLA-4 on monocytes andlymphocytes, but no neutrophils, VCAM-1 is important in mediating theselective adhesion of mononuclear leukocytes. Subsequent conversion ofleucocytes to foamy macrophages results in the synthesis of a widevariety of inflammatory cytokines, growth factors, and chemoattractantsthat help propagate the leukocyte and platelet recruitment, smoothmuscle cell proliferation, endothelial cell activation, andextracellular matrix synthesis characteristic of maturingatherosclerotic plaque.

VCAM-1 is a mediator in chronic inflammatory disorders such as asthma,rheumatoid arthritis and autoimmune diabetes. For example, it is knownthat the expression of VCAM-1 and ICAM-1 are increased in asthmatics.Pilewski, J. M., et al. Am J. Respir. Cell Mol. Biol. 12, 1-3, (1995);Ohkawara, Y., et al., Am. J. Respir. Cell Mol. Biol. 12, 4-12, (1995).Additionally, blocking the integrin receptors for VCAM-1 and ICAM-1(VLA-4 and LFA-1, respectively) suppressed both early and late phaseresponses in an ovalbumin-sensitized rat model of allergic airwayresponses. Rabb, 11.A., et al., Am. J. Respir. Care Med. 149, 1186-1191) (1994). There is also increased expression of endothelial adhesionmolecules, including VCAM-1, in the microvasculature of rheumatoidsynovium. Koch, A. E. et al., Lab. Invest. 64, 313-322 (1991);Morales-Ducret, J. et al., Immunol. 149, 1421-1431 (1992). Neutralizingantibodies directed against VCAM-1 or its counter receptor, VLA-4, candelay the onset of diabetes in a mouse model (NOD mice) whichspontaneously develop the disease. Yang, X. D. et al., Proc. Natl. Acad.Sci. U.S.A. 90, 10494-10498 (1993); Burkly, L. C. et al., Diabetes 43,523-534 (1994); Baron, J. L. et al., J. Clin. Invest, 93, 1700-1708(1994). Monoclonal antibodies to VCAM-1 can also have a beneficialeffect in animal models of allograft rejection, suggesting thatinhibitors of VCAM-1 expression may have utility in preventingtransplant rejection. Oroez, C. G. et al., Immunol. Lett. 32, 7-12(1992).

VCAM-1 is expressed by cells both as a membrane bound form and as asoluble form. The soluble form of VCAM-1 has been shown to inducechemotaxis of vascular endothelial cells in vitro and stimulate anangiogenic response in rat cornea. Koch, A. F. et al., Nature 376,517-519 (1995). Inhibitors of the expression of soluble VCAM-1 havepotential therapeutic value in treating disease with a strong angiogeniccomponent, including tumor growth and metastasis. Folkman, J., andShing, Y., Biol. Chem. 10931-10934 (1992).

VCAM-1 is expressed in cultured human vascular endothelial cells afteractivation by lipopolysaccharide (LPS) and cytokines such asinterleukin-1 (IL-1) and tumor necrosis factor (TNF-α). These factorsare not selective for activation of cell adhesion molecule expression.

U.S. Pat. No. 5,380,747 to Medford, et al., teaches the use ofdithiocarbamates such as pyrrolidine dithiocarbamate for the treatmentof cardiovascular and other inflammatory diseases.

U.S. Pat. No. 5,750,351 to Medford, et al., and WO95/30415 to EmoryUniversity describe the discovery that polyunsaturated fatty acids(“PUFAs”) and their hydroperoxides (“ox-PUFAs”), which are importantcomponents of oxidatively modified low density lipoprotein (LDL), inducethe expression of VCAM-1, but not intracellular adhesion molecule-1(ICAM-1) or E-selectin in human aortic endothelial cells, through amechanism that is not mediated by cytokines or other noncytokinesignals. This is a fundamental discovery of an important and previouslyunknown biological pathway in VCAM-1 mediated immune responses.

As non-limiting examples, linoleic acid, linolenic acid, arachidonicacid, linoleyl hydroperoxide (13-HPODE) and arachidonic hydroperoxide(15-HPETE) induce cell-surface gene expression of VCAM-1 but not ICAM-1or E-selectin. Saturated fatty acids (such as stearic acid) andmonounsaturated fatty acids (such as oleic acid) do not induce theexpression of VCAM-1, ICAM-1 or E-selectin.

The induction of VCAM-1 by PUFAs and their fatty acid hydroperoxides issuppressed by dithiocarbamates, including pyrrolidine dithiocarbamate(PDTC). This indicates that the induction is mediated by an oxidizedsignal molecule, and that the induction is prevented when the oxidationof the molecule is blocked (i.e., the oxidation does not occur),reversed (i.e., the signal molecule is reduced), or when the redoxmodified signal is otherwise prevented from interacting with itsregulatory target.

Cells that are chronically exposed to higher than normal levels ofpolyunsaturated fatty acids or their oxidized counterparts can initiatean immune response that is not normal and which is out of proportion tothe threat presented, leading to a diseased state. The oversensitizationof vascular endothelial cells to PUFAs and ox-PUFAs can accelerate theformation, for example, of atherosclerotic plaque.

Based on these discoveries, a method for the treatment ofatherosclerosis, post-angioplasty restenosis, coronary artery disease,angina, small artery disease and other cardiovascular diseases, as wellas non cardiovascular inflammatory diseases that are mediated by VCAM-1,was described in WO95/30415 that includes the removal, decrease in theconcentration of, or prevention of the formation of oxidizedpolyunsaturated fatty acids including but not limited to oxidizedlinoleic (C₁₈Δ^(9,12)), linolenic (C₁₈Δ^(6,9,12)), arachidonic(C₂₀Δ^(5,8,11,14)) and eicosatrienoic (C₂₀Δ^(8,1,14)) acids.

Nonlimiting examples of noncardiovascular inflammatory diseases that aremediated by VCAM-1 include rheumatoid and osteoarthritis, asthma,dermatitis, and multiple sclerosis.

Hypercholesterolemia and hyperlipidemia

Hypercholesterolemia is an important risk factor associated withcardiovascular disease. Serum lipoproteins are the carriers for lipidsin the circulation. Lipoproteins are classified according to theirdensity: chylomicrons, very low-density lipoproteins (VLDL), low densitylipoproteins (LDL) and high-density lipoproteins (HDL). Chylomicronsprimarily participate in transporting dietary triglycerides andcholesterol from the intestine to adipose tissue and liver. VLDL deliverendogenously synthesized triglycerides from liver to adipose and othertissues. LDL transports cholesterol to peripheral tissues and regulateendogenous cholesterol levels in those tissues. HDL transportscholesterol from peripheral tissues to the liver. Arterial wallcholesterol is derived almost exclusively from LDL. Brown and Goldstein,Ann. Rev. Biochem. 52, 223 (1983); Miller, Ann. Rev. Med. 31, 97 (1980).In patients with low levels of LDL, the development of atherosclerosisis rare.

Steinberg, et al., (N. Eng. J. Med. 1989; 320:915-924) hypothesized thatmodification of low-density lipoprotein (LDL) into oxidatively modifiedLDL (ox-LDL) by reactive oxygen species is the central event thatinitiates and propagates atherosclerosis. Oxidized LDL is a complexstructure consisting of at least several chemically distinct oxidizedmaterials, each of which, alone or in combination, may modulatecytokine-activated adhesion molecule gene expression. R fatty acidhydroperoxides such as linoleyl hydroperoxide (13-HPODE) are producedfrom free fatty acids by lipoxygenases and are an important component ofoxidized LDL.

It has been proposed that a generation of oxidized lipids is formed bythe action of the cell lipoxygenase system and that the oxidized lipidsare subsequently transferred to LDL. There is thereafter a propagationreaction within the LDL in the medium catalyzed by transition metalsand/or sulfhydryl compounds. Previous investigations have demonstratedthat fatty acid modification of cultured endothelial cells can altertheir susceptibility to oxidant injury, whereas supplementation withpolyunsaturated fatty acids (PUFA) enhances susceptibility to oxidantinjury. Supplementation of saturated or monounsaturated fatty acids tocultured endothelial cells reduces their susceptibility to oxidantinjury, whereas supplementation with polyunsaturated fatty acids (PUFA)enhances susceptibility to oxidant injury.

Using reverse-phase HPLC analysis of native and saponified liquidextracts of LDL, it has been demonstrated that 13-HPODE is thepredominant oxidized fatty acid in LDL oxidized by activated humanmonocytes. Chronic exposure to oxidized LDL provides an oxidative signalto vascular endothelial cells, possible through a specific fatty acidhydroperoxide, that selectively augments cytokine-induced VCAM-1 geneexpression.

Through a mechanism that is not well defined, areas of vessel wallpredisposed to atherosclerosis preferentially sequester circulating LDL.Through a poorly understood pathway, endothelial, smooth muscle, and/orinflammatory cells then convert LDL to ox-LDL. In contrast to LDL, whichis taken up through the LDL receptor, monocytes avidly take up ox-LDLthrough a “scavenger” receptor whose expression, unlike the LDLreceptor, is not inhibited as the content of intracellular lipid rises.Thus, monocytes continue to take up ox-LDL and become lipid-engorgedmacrophage-foam cells that form the fatty streak.

There is now a large body of evidence demonstrating thathypercholesterolemia is an important risk factor associated with heartdisease. For example, in December 1984, a National Institute of HealthConsensus Development Conference Panel concluded that loweringdefinitely elevated blood cholesterol levels (specifically blood levelsof low-density lipoprotein cholesterol) will reduce the risk of heartattacks due to coronary heart disease.

Typically, cholesterol is carried in the blood of warm-blooded animalsin certain lipid-protein complexes such as chylomicrons, very lowdensity lipoprotein (VLDL), low density lipoprotein (LDL), and highdensity lipoprotein (HDL). It is widely accepted that LDL functions in away that directly results in deposition of the LDL cholesterol in theblood-vessel wall and that HDL functions in a way that results in theHDL picking up cholesterol from the vessel wall and transporting it tothe liver where it is metabolized [Brown and Goldstein, Ann. Rev.Biochem. 52, 223 (1983); Miller, Ann. Rev. Med. 31, 97 (1980)]. Forexample, in various epidemiologic studies the LDL cholesterol levelscorrelate well with the risk of coronary heart disease whereas the HDLcholesterol levels are inversely associated with coronary heart disease[Patton et al., Clin. Chem. 29, 1980 (1983)]. It is greatly accepted bythose skilled in the art that reduction of abnormally high LDLcholesterol levels is effective therapy not only in the treatment ofhypercholesterolemia but also in the treatment of atherosclerosis.

Furthermore, there is evidence based on animal and laboratory findingsthat peroxidation of LDL lipid, such as the unsaturated fatty acidportions of LDL cholesteryl esters and phospholipids, facilitate theaccumulation of cholesterol in monocyte/macrophages which eventually aretransformed into foam cells and become deposited in the sub-endothelialspace of the vessel wall. The accumulation of foam cells in the vesselwall is recognized as an early event in the formation of anatherosclerotic plaque. Thus it is believed that peroxidation of LDLlipid is an important prerequisite to the facilitated accumulation ofcholesterol in the vessel wall and the subsequent formation of anatherosclerotic plaque. For example, it has been shown thatmonocyte/macrophages take up and degrade native LDL at relatively lowrates and without marked accumulation of cholesterol. In contrast,oxidized LDL is taken up by these monocyte/macrophages at much higherrates and with marked accumulation of cholesterol [Parthasarathy et al.,J. Clin. Invest. 77,641 (1986)]. It is therefore desirable to providemethods of inhibiting LDL lipid peroxidation in a patient in needthereof.

Elevated cholesterol levels are associated with a number of diseasestates, including restenosis, angina, cerebral atherosclerosis, andxanthoma. It is desirable to provide a method for reducing plasmacholesterol in patients with, or at risk of developing, restenosis,angina, cerebral arteriosclerosis, xanthoma, and other disease statesassociated with elevated cholesterol levels.

Since it has been determined that hypercholesterolemia is due toelevated LDL (hyperlipidemia), the lowering of LDL levels by dietarytherapy is attempted. There are several drug classes that are commonlyused to lower LDL levels, including bile acid sequestrants, nicotinicacid (niacin), and 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA)reductase inhibitors. Probucol and the fibrate derivatives are sometimesused as adjunctive therapy, usually in combination with othermedications. The HMG CoA reductase inhibitors have been termed statinsor vastatins. Statins are among the most effective agents currently onthe market for hypercholesterolemia, and include pravastatin (Pravchol,Bristol Myers Squibb), atorvastatin (Warner Lambert/Pfizer), simvastatin(Zocor, Merck), lovastatin (Mevacor, Merck), and fluvastatin (Lescol).

Evidence suggests that the atherogenic effects of low densitylipoprotein (LDL) may be in part mediated through its oxidativemodification. Probucol has been shown to possess potent antioxidantproperties and to block oxidative modification of LDL. Consistent withthese findings, probucol has been shown to actually slow the progressionof atherosclerosis in LDL receptor-deficient rabbits as discussed inCarew et al. Proc. Natl. Acad. Sci. U.S.A. 84:7725-7729 (1987). Mostlikely, probucol is effective because it is highly lipid soluble and istransported by lipoproteins, thus protecting them against oxidativedamage.

Probucol is chemically related to the widely used food additives2,[3]-tert-butyl-4-hydroxyanisole (BHA) and 2,6-di-tert-butyl-4-methylphenol (BHT). Its full chemical name is 4,4′-(isopropylidenedithio)bis(2,6-di-tert-butylphenol).

Probucol is used primarily to lower serum cholesterol levels inhypercholesterolemic patients. Probucol is commonly administered in theform of tablets available under the trademark Lorelco™. Unfortunately,probucol is almost insoluble in water and therefore cannot be injectedintravenously. In fact, probucol is difficult for cells to absorb invitro because of its poor miscibility in buffers and media for cellculture. Solid probucol is poorly absorbed into the blood, and isexcreted in substantially unchanged form. Further, the tablet form ofprobucol is absorbed at significantly different rates and in differentamounts by different patients. In one study (Heeg, et al., Plasma Levelsof Probucol in Man After Single and Repeated Oral Doses, La NouvellePresse Medicale, 9:2290-2294 (1980)), peak levels of probucol in serawere found to differ as much as a factor of 20 from patient to patient.In another study, Kazuyza et al., J. Lipid Res. 32; 197-204 (1991)observed an incorporation of less than about 1 μg of probucol/10⁶ cellswhen endothelial cells are incubated for 24 h with 50 μM probucol.

U.S. Pat. No. 5,262,439 to Parthasarathy discloses analogs of probucolwith increased water solubility in which one or both of the hydroxylgroups are replaced with ester groups that increase the water solubilityof the compound. In one embodiment, the derivative is selected from thegroup consisting of a mono- or di-probucol ester of succinic acid,glutaric acid, adipic acid, seberic acid, sebacic acid, azelaic acid, ormaleic acid. In another embodiment, the probucol derivative is a mono-or di- ester in which the ester contains an alkyl or alkenyl group thatcontains a functionality selected from the group consisting of acarboxylic acid group, amine group, salt of an amine group, amidegroups, amide groups and aldehyde groups.

A series of French patents disclose that certain probucol derivativesare hypocholesterolemic and hypolipemic agents: Fr 2168137 (bis4-hydroxyphenylthioalkane esters); Fr 2140771 (tetralinyl phenoxyalkanoic esters of probucol); Fr 2140769 (benzofuryloxyalkanoic acidderivatives of probucol); Fr 2134810(bis-(3-alkyl-5-t-alkyl-4-thiazole-5-carboxy)phenylthio)alkanes; FR2133024 (bis-(4-nicotinoyloxyphenylthio)propanes; and Fr 2130975(bis(4-phenoxyalkanoyloxy)-phenylthio)alkanes).

U.S. Pat. No. 5,155,250 to Parker, et al. discloses that2,6-dialkyl-4-silylphenols are antiatherosclerotic agents. The samecompounds are disclosed as serum cholesterol lowering agents in PCTPublication No. WO 95/15760, published on Jun. 15, 1995. U.S. Pat. No.5,608,095 to Parker, et al. discloses that alkylated-4-silyl-phenolsinhibit the peroxidation of LDL, lower plasma cholesterol, and inhibitthe expression of VCAM-1, and thus are useful in the treatment ofatherosclerosis.

A series of European patent applications and to Shinogi SeiyakuKabushiki Kaisha disclose phenolic thioesters for use in treatingarteriosclerosis. European Patent Application No. 348 203 disclosesphenolic thioesters which inhibit the denaturation of LDL and theincorporation of LDL by macrophages. The compounds are useful asanti-arteriosclerosis agents. Hydroxamic acid derivatives of thesecompounds are disclosed in European Patent Application No. 405 788 andare useful for the treatment of arteriosclerosis, ulcer, inflammationand allergy. Carbamoyl and cyano derivatives of the phenolic thioestersare disclosed in U.S. Pat. No. 4,954,514 to Kita, et al.

U.S. Pat. No. 4,752,616 to Hall, et al., disclosearylthioalkylphenylcarboxylic acids for the treatment of thromboticdisease. The compounds disclosed are useful as platelet aggregationinhibitors for the treatment of coronary or cerebral thromboses and theinhibition of bronchoconstriction, among others.

A series of patents to Adir et Compagnie disclose substitutedphenxoyisobutyric acids and esters useful as antioxidants andhypolipaemic agents. This series includes U.S. Pat. Nos. 5,206,247 and5,627,205 to Regnier, et al. (which corresponds to European PatentApplication No. 621 255) and European Patent Application No. 763 527.

WO97/15546 to Nippon Shinyaku Co. Ltd. discloses carboxylic acidderivatives for the treatment of arterial sclerosis, ischemic heartdiseases, cerebral infarction and post PTCA restenosis.

The Dow Chemical Company is the assignee of patents to hypolipidemic2-(2,5-di-tert-butyl-4-hydroxyphenyl)thio carboxamides. For example,U.S. Pat. No. 4,029,812, 4,076,841 and 4,078,084 to Wagner et al.,disclose these compounds for reducing blood serum lipids, especiallycholesterol and triglyceride levels.

Given that cardiovascular disease is currently the leading cause ofdeath in the United States, and ninety percent of cardiovascular diseaseis presently diagnosed as atherosclerosis, there is a strong need toidentify new methods and pharmaceutical agents for its treatment.Important to this goal is the identification and manipulation of thespecific oxidized biological compounds that act as selective regulatorsof the expression of mediators of the inflammatory process, and inparticular, VCAM-1. A more general goal is to identify selective methodsfor suppressing the expression of redox sensitive genes or activatingredox sensitive genes that are suppressed.

It is therefore an object of the present invention to provide newcompounds, compositions and methods for the treatment of cardiovascularand inflammatory diseases.

It is still another object of the present invention to provide newcompounds and compositions which are useful as inhibitors of LDL lipidperoxidation.

It is still another object of the present invention to provide newcompounds and compositions which are useful as antiatheroscleroticagents.

It is still another object of the present invention to provide newcompounds and compositions which are useful as LDL lipid loweringagents.

It is still another object of the present invention to provide newcompounds, compositions and methods for selectively inhibiting theexpression of VCAM-1.

It is still another object of the present invention to provide a methodfor the treatment of a disease that is mediated by the expression orsuppression of a redox sensitive gene, for example MCP-1, IL-6 andthrombin receptor.

SUMMARY OF THE INVENTION

The present invention provides a compound, composition and method forinhibiting the expression of VCAM-1, and thus can be used in thetreatment of a disease mediated by VCAM-1, which includes administeringa compound of formula (I) or (II), or a pharmaceutically acceptable saltthereof, optionally in a pharmaceutically acceptable carrier. Thecompounds of formula (I) are

wherein

X is O, S, SO, SO₂, CH₂, or NH;

Spacer is a group selected from the group consisting of —(CH₂)_(n)—,—(CH₂)_(n)—CO—, —(CH₂)_(n)—N—, —(CH₂)_(n)—O—, —(CH₂)_(n)—S—, —(CH₂O)—,—(OCH₂)—, —(SCH₂)—, —(CH₂S—), —(aryl-O)—, —(O-aryl)—, —(alkyl-O)—,—(O-alkyl)—;

n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

Y is substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted alkyl, substituted orunsubstituted alkoxy, substituted or unsubstituted alkoxyalkyl,substituted or unsubstituted alkylthio, substituted or unsubstitutedalkylthioalkyl, substituted or unsubstituted alkylsulfinyl, substitutedor unsubstituted alkylsulfinylalkyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted alkylsulfonylalkyl, NH₂,NHR, NR₂, SO₂—OH, OC(O)R, C(O)OH, C(O)OR, (C(O)NH₂, C(O)NHR, C(O)NR₂,SO₂NH₂, SO₂NHR, SO₂NR₂;

R is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, alkyl-COOH, alkyl-COOalkyl,alkyl-COOaryl, heteroaryl, substituted heteroaryl, or when attached to anitrogen atom, two adjacent R groups may combine to form a ring of 5 to7 members;

R¹ and R² are independently straight chained, branched, or cyclic alkylwhich may be substituted, aryl, substituted aryl, heteroaryl,substituted heteroaryl, alkaryl, or aralkyl; and wherein substituents onthe R¹ or R² groups are selected from the group consisting of hydrogen,halogen, alkyl, nitro, amino, alkylamino, dialkylamino, acyl, andacyloxy;

R³ and R⁴ are independently any group that does not otherwise adverselyaffect the desired properties of the molecule, including H, halogen orR¹.

The compound of formula (II) has the following structure

wherein

R_(a), R_(b), R_(c), and R_(d) are independently any group that does nototherwise adversely affect the desired properties of the molecule,including hydrogen, straight chained, branched, or cyclic alkyl whichmay be substituted, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, alkaryl, substituted alkaryl, aralkyl or substitutedaralkyl; substituents on the R_(a), R_(b), R_(c) and R_(d) groups areselected from the group consisting of hydrogen, halogen, alkyl, nitro,amino, haloalkyl, alkylamino, dialkylamino, acyl and acyloxy;

Z is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,aralkyl, alkaryl, heteroaryl, heteroaralkyl, a carbohydrate group,—(CH₂)—R_(e), —C(O)—R_(g), and —C(O)—(CH₂)_(n)—R_(h), wherein (a) wheneach of R_(a), R_(b), R_(c), and R_(d) are t-butyl, Z cannot by hydrogenand (b) when each of R_(a), R_(b), R_(c), and R_(d) are t-butyl, Zcannot be the residue of succinic acid;

R_(e) is selected from the group consisting of alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy,substituted alkyloxy, alkoxyalkyl, substituted alkoxyalkyl, NH₂, NHR,NR₂, mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, acyloxy, substituted acyloxy, COOH,COOR, —CH(OH)R_(k), hydroxy, C(O)NH₂, C(O)NHR, C(O)NR₂;

R_(g) is selected from the group consisting of alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy,substituted alkyloxy, alkoxyalkyl, substituted alkoxyalkyl, NH₂, NHR,NR₂, mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl;

R_(h) is selected from the group consisting of alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy,substituted alkyloxy, alkoxyalkyl, substituted alkoxyalkyl, NH₂, NHR,NR₂, mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, acyloxy, substituted acyloxy, COOH,COOR, —CH(OH)R_(k), hydroxy, O-phosphate, C(O)NH₂, C(O)NHR, C(O)NR₂ andpharmaceutically acceptable salts thereof;

Or, in an alternative embodiment, R₃, R_(g), and R_(h) can independentlybe a substituent which improves the water solubility of the compound,including, but not limited to C(O)—spacer—SO₃H, wherein spacer is asdefined above, C(O)-spacer—SO₃M, wherein M is a metal used to form apharmaceutically acceptable salt, for example sodium, C)O)-spacer-PO₃H₂,C(O)-spacer-PO₃M₂, C(O)-spacer-PO₃HM, C(O)-spacer-PO₄H,C(O)-spacer-PO₄M, SO₃M,—PO₃H₂—PO₃M₂, —PO₃HM, cyclic phosphates,polyhydroxyalkyl, carbohydrate groups,C(O)-spacer-[O(C₁₋₃alkyl)_(p)]_(n), wherein n is as defined above and pis 1, 2 or 3, —[O(C₁₋₃alkyl)_(p)]_(n), carboxy lower alkyl, loweralkylcarbonyl lower alkyl, N, N-dialkyl amino lower alkyl, pyridyl loweralkyl, imidazolyl lower alkyl, morpholinyl lower alkyl, pyrrolidinyllower alkyl, thiazolinyl lower alkyl, piperidinyl lower alkyl,morpholinyl lower hydroxyalkyl, N-pyrryl, piperazinyl lower alkyl,N-alkyl piperazinyl lower alkyl, triazolyl lower alkyl, tetrazolyl loweralkyl, tetrazolylamino lower alkyl, or thiazolyl lower alkyl.

The present invention generally provides a method for treatingcardiovascular and inflammatory disorders in a patient in need thereofcomprising administering to said patient an effective amount of acompound of formula (I) or formula (II).

The present invention further provides a method of inhibiting theperoxidation of LDL lipid in a patient in need thereof comprisingadministering to said patient an effective antioxidant amount of acompound of formula (I) or formula (II).

In an alternative embodiment, a method is provided for suppressing theexpression of a redox-sensitive gene or activating a gene that issuppressed through a redox-sensitive pathway, that includesadministering an effective amount to prevent the oxidation of theoxidized signal, and typically, the oxidation of a PUFA of a compound offormula (I) or formula (II). Representative redox-sensitive genes thatare involved in the presentation of an immune response include, but arenot limited to, those expressing cytokines involved in initiating theimmune response (e.g., IL-1β), chemoattractants that promote themigration of inflammatory cells to a point of injury (e.g., MCP-1),growth factors (e.g., Il-6 and the thrombin receptor), and adhesionmolecules (e.g., VCAM-1 and E-selectin).

DETAILED DESCRIPTION OF THE INVENTION

The term alkyl, as used herein, unless otherwise specified, refers to asaturated straight, branched, or cyclic, primary, secondary, or tertiaryhydrocarbon of C₁ to C₁₀, and specifically includes methyl, ethyl,propyl, isopropyl, cyclopropyl, butyl, isobtyl, t-butyl, pentyl,cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl,cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl, and2,3-dimethylbutyl. The alkyl group can be optionally substituted withone or more moieties selected from the group consisting of alkyl, halo,hydroxyl, carboxyl, acyl, acyloxy, amino, alkylamino, arylamino, alkoxy,aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid,phosphate, or phosphonate, either unprotected, or protected asnecessary, as known to those skilled in the art, for example, as taughtin Greene, et al., Protective Groups in Organic Synthesis, John Wileyand Sons, Second Edition 1991, hereby incorporated by reference.

The term lower alkyl, as used herein, and unless otherwise specified,refers to a C₁ to C₅ saturated straight, branched, or if appropriate, acyclic (for example, cycloproyl) alkyl group.

Likewise the term alkylene refers to a saturated hydrocarbyldiyl radicalof straight or branched configuration made up of from one to ten carbonatoms. Included within the scope of this term are methylene,1,2-ethane-diyl, 1,1-ethane-diyl, 1,3-propane-diyl, 1,2-propane-diyl,1,3-butane-diyl, 1,4-butane-diyl and the like. The alkylene group can beoptionally substituted with one or more moieties selected from the groupconsisting of alkyl, halo, hydroxyl, carboxyl, acyl, acyloxy, amino,alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid,sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected,or protected as necessary, as known to those skilled in the art, forexample, as taught in Greene, et al., Protective Groups in OrganicSynthesis, John Wiley and Sons, Second Edition, 1991, herebyincorporated by reference.

The term “—(CH₂)_(n)—” represents a saturated hydrocarbyldiyl radical ofstraight chain configuration. The term “n” is defined as 0-10. Themoiety “—(CH₂)_(n)—” thus represents a bond (i.e., when n=0), methylene,1,2-ethanediyl or 1,3-propanediyl, etc.

The term aryl, as used herein, and unless otherwise specified, refers tophenyl, biphenyl, or naphthyl, and preferably phenyl. The term aralkyl,as used herein, and unless otherwise specified, refers to an aryl groupas defined above linked to the molecule through an alkyl group asdefined above. The term alkaryl, as used herein, and unless otherwisespecified, refers to an alkyl group as defined above linked to themolecule through an aryl group as defined above. In each of thesegroups, the alkyl group can be optionally substituted as describe aboveand the aryl group can be optionally substituted with one or moremoieties selected from the group consisting of alkyl, halo, hydroxyl,carboxyl, acyl, acyloxy, amino, alkylamino, arylamino, alkoxy, aryloxy,nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, orphosphonate, either unprotected, or protected as necessary, as known tothose skilled in the art, for example, as taught in Green, et al.,Protective Groups in Organic Synthesis, John Wiley and Sons, SecondEdition, 1991. Specifically included within the scope of the term arylare phenyl; naphthyl; phenylmethyl; phenylethyl 3,4,5-trihydroxyphenyl;3,4,5-trimethoxyphenyl; 3,4,5-triethoxyphenyl; 4-cholorophenyl;4-methylphenyl; 3,5-di-tertiarybutyl-4-hydroxyphenyl; 4-fluorophenyl;4-chloro-1-naphthyl; 2-methyl-1-naphthylmethyl; 2-naphthylmethyl;4-chlorophenylmethyl; 4-tertiarybutylphenyl; 4-tertiarybutylphenylmethyland the like.

The term “protected” as used herein and unless otherwise defined refersto a group that is added to an oxygen, nitrogen, or phosphorus atom toprevent its further reaction or for other purposes. A wide variety ofoxygen and nitrogen protecting groups are known to those skilled in theart of organic synthesis.

The term halo, as used herein, include chloro, bromo, iodo, and fluoro.

The term alkoxy, as used herein and unless otherwise specified, refersto a moiety of the structure —o-alkyl, wherein alkyl is as definedabove.

The term acyl, as used herein, refers to a group of the formula C(O)R′,wherein R′ is an alkyl, aryl, alkaryl, or aralkyl, group, or substitutedalkyl, aryl, aralkyl, or alkaryl, wherein these groups are as definedabove.

As used herein, the term polyunsaturated fatty acid PUFA) refers to afatty acid (typically C₈ to C₂₄) that has at least two alkenyl bonds,and includes but is not limited to linoleic (C₁₈Δ^(9,12)), linolenic(C₁₈Δ^(6,9,12)), arachidonic (C₂₀Δ^(8,11,14)) acids.

The term oxidized polyunsaturated fatty acid (ox-PUFA) refers to anunsaturated fatty acid in which at least on of the alkenyl bonds hasbeen converted to a hydroperoxide. Nonlimiting examples are 13-HPODE and15-HPETE.

The term pharmaceutically acceptable salts or complexes refers to saltsor complexes that retain the desired biological activity of thecompounds of the present invention and exhibit minimal undesiredtoxicological effects. Nonlimiting examples of such salts are (a) acidaddition salts formed with inorganic acids (for example, hydrochloricacid, hydrobromic acid, sulfuric acid, phosphonic acid, nitric acid, andthe like), and salts formed with organic acids such as acetic acid,oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid,benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid,naphthalenesulfonic acid, naphthalenedisulfonic acid, andpolygalcturonic acid; (b) base addition salts formed with metal cationssuch as zinc, calcium, bismuth, barium, magnesium, aluminum, copper,cobalt, nickel, cadmium, sodium, potassium, and the like, or with acation formed from ammonia, N,N-dibenzylethylenediamine, D-glucosamine,tetraethylammonium, or ethylenediamine; or (c) combinations of (a) and(b); e.g., a zinc tannate salt or the like. Also included in thisdefinition are pharmaceutically acceptable quaternary salts known bythose skilled in the art, which specifically include the quaternaryammonium salt of the formula —NR⁺A⁻; wherein R is as defined above and Ais counterion, including chloride, bromide, iodide, -O-alkyl,toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate(such as benzoate, succinate, acetate, glycolate, maleate, malate,citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate,benzyloate, and diphenylacetate).

Diseases mediated by the VCAM-1 include, but are not limited toatherosclerosis, post-angioplasty restenosis, coronary artery disease,angina, small artery disease, and other cardiovascular diseases, as wellas non cardiovascular inflammatory diseases such as rheumatoidarthritis, osteoarthritis, asthma, dermatitis, multiple sclerosis andpsoriasis.

In one embodiment, the invention is a method for treating a diseasemediated by the expression of VCAM-1 comprising administering a compoundof the formula

wherein

X is O, S, SO, SO₂, CH₂, or NH;

Spacer is a group selected from the group consisting of —(CH₂)_(n);—(CH₂)_(n)—CO—, —(CH₂)_(n)—N—, —(CH₂)_(n)—O—, —(CH₂)_(n)—S—, —(CH₂O)—,—(OCH₂)—, —(SCH₂)—, —(CH₂S—), —(aryl-O)—, —(O-aryl)—, —(alkyl-O)—,—(O-alkyl)—;

n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

Y is substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted alkyl, NH₂, NHR, NR₂, SO₂—OH,OC(O)R, C(O)OH, C(O)OR, C(O)NH₂, C(O)NHR, C(O)RH₂;

R is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, alkyl-COOH, alkyl-COOalkyl,alkyl-COOaryl, heteroaryl, substituted heteroaryl, or when attached to anitrogen atom, two adjacent R groups may combined to form a ring of 5 to7 members;

R¹ and R² are independently straight chained, branched, or cyclic alkylwhich may be substituted, aryl, substituted aryl, heteroaryl,substituted heteroaryl, alkaryl, or aralkyl; and wherein substituents onthe R¹ or R² groups are selected from the group consisting of hydrogen,halogen, alkyl, nitro, amino, alkylamino, dialkylamino, acyl, andacyloxy;

R³ and R⁴ are independently any group that does not otherwise adverselyaffect the desired properties of the molecule, including H, halogen, orR¹.

Preferred compounds of the present invention include compounds offormula (I) wherein

X is S, SO or SO₂; Spacer is —(CH₂)_(n)— or —(CH₂)_(n)CO—; n is 0-10; Yis aryl, substituted aryl, heteroaryl, substituted heteroaryl, NH₂, NHR,NR₂, alkyl, substituted alkyl, acyloxy, and substituted acyloxy; R isalkyl, alkenyl, alkynyl, aryl, alkyl,-COOH, alkyl-COOalkyl,alkyl-COOaryl, heteroaryl, or nitro substituted heteroaryl, or whenattached to a nitrogen atom, two adjacent R groups may combine to form aring of 5 to 7 members; R¹ and R² are independently straight chained,branched or cyclic C₁₋₁₀ alkyl; R³ and R⁴ are independently hydrogen,halogen or R¹.

Another preferred embodiment of the present invention includes compoundsof formula (I) wherein X is S, SO, or SO₂; Spacer is —(CH₂)_(n)— or—(CH₂)_(n)—CO—; n is 0-10; Y is aryl, substituted aryl, heteraryl,substituted heteroaryl, NH₂, NHR, NR₂, alkyl, substituted alkyl,acyloxy, and substituted acyloxy; R is alkyl, alkenyl, alkynyl, aryl,alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, heteroaryl, or nitrosubstituted heteroaryl, or when attached to a nitrogen atom, twoadjacent R groups may combine to form a ring of 5 to 7 members; R¹ andR² are independently straight chained, branched or cyclic C₁₋₅ alkyl; R³and R⁴ are independently H.

Another preferred embodiment of the present invention includes compoundsof formula (I) wherein X is S, SO, or SO₂; Spacer is —(CH₂ _(n)— or—(CH₂)_(n)—CO—; n is 0-10; Y is aryl; aryl which is mono- orpolysubstituted by alkyl, alkenyl, alkynyl, halo, nitro, hydroxy, COOH,COOR, CONH₂, CONHR, CONHR₂, —(CH₂)_(m)—OH wherein m is 0-10, haloalkyl,mono- or poly-hydroxysubstituted branched alkyl, a carbohydrate group,SO₂OH, SO₂NH₂, SO₂NHR, SO₂NR₂, or OCOR; heteroaryl; heteroaryl which ismono- or polysubstituted by alkyl, alkenyl, alkynyl CH₂NH₂, CH₂NHR,CH₂NR₂, COOH, COOR; NH₂; NHR: NR₂; straight chained, branched or cyclicalkyl; straight chained, branched, or cyclic alkyl substituted by OCOR,SO₂OH, COOH or COOR; and OCOR; R is alkyl, alkenyl, alkynyl, aryl,alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, heteroaryl, or nitrosubstituted heteroaryl, or when attached to a nitrogen atom, twoadjacent R groups may combine to form a ring of 5 to 7 members; R¹ andR² are independently C₁₋₅ alkyl; R³ and R⁴ are independently H.

Another preferred embodiment of the present invention includes compoundsof formula (I) wherein X is S, SO, or SO₂; Spacer is —(CH₂)_(n)— or—(CH₂)_(n)—CO—; n is 0-10; Y is aryl; aryl which is mono- orpolysubstituted by alkyl, alkenyl, alkynyl, halo, nitro, hydroxy, COOH,COOR, CONH₂, CONHR, CONR₂, —(CH₂)_(m)—OH wherein m is 0-10, haloalkyl,mono- or poly-hydroxysubstituted branched alkyl, a carbohydrate group,SO₂OH, SO₂NH₂, SO₂NHR, SO₂NR₂, or OCOR; R is alkyl, alkenyl, alkynyl,aryl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, heteroaryl, or nitrosubstituted heteroaryl, or when attached to a nitrogen atom, twoadjacent R groups may combine to form a ring of 5 to 7 members; R¹ andR² are independently C₁₋₅ alkyl; R³ and R⁴ are independently H.

Another preferred embodiment of the present invention includes compoundsof formula (I) wherein X is S, SO, or SO₂; Spacer is —(CH₂)_(n)— or—(CH₂)_(n)—CO—; n is 0-10; Y is phenyl; phenyl which is mono- orpolysubstituted by alkyl, alkenyl, alkynyl, halo, nitro, hydroxy, COOH,COOR, CONH₂, CONHR, CONR₂, —(CH₂)_(m)—OH wherein m is 0-10, haloalkyl,mono- or poly-hydroxysubstituted branched alkyl, a carbohydrate group,SO₂OH, SO₂NH₂, SO₂NHR, SO₂NR₂, or OCOR; R is alkyl, alkenyl, alkynyl,alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, aryl, heteroaryl ornitro-substituted heteroaryl, or when attached to a nitrogen atom, twoadjacent R groups may combine to form a ring of 5 to 7 members; R¹ andR² are independently C₁₋₅ alkyl; R³ and R⁴ are independently H.

Another preferred embodiment of the present invention includes compoundsof formula (I) wherein X is S, SO, or SO₂, Spacer is —(CH₂)_(m)—; n is0-10; Y is phenyl; phenyl which is mono- or polysubstituted by alkyl,alkenyl, alkynyl, halo, nitro, hydroxy, COOH, COOR, CONH₂, CONHR, CONR₂,—(CH₂)_(m)—OH wherein m is 0-10, haloalkyl, mono- orpoly-hydroxysubstituted branched alkyl, a carbohydrate group, SO₂OH,SO₂NH₂, SO₂NHR, SO₂NR₂, or OCOR; R is alkyl, alkenyl, alkynyl,alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, aryl heteroaryl ornitro-substituted heteroaryl, or when attached to a nitrogen atom, twoadjacent R groups may combine to form a ring of 5 to 7 members; the Rgroup may be further substituted by alkyl, alkyl-COOH, alkyl-COOalkyl,or alkyl-COOaryl; R¹ and R² are independently C₁₋₅ alkyl; R³ and R⁴ areindependently H.

Another preferred embodiment of the present invention includes compoundsof formula (I) wherein X is S, SO, or SO₂; Spacer is —(CH₂)_(n)—CO—; nis 0-10; Y is phenyl; phenyl which is mono- or polysubstituted by alkyl,alkenyl, alkynyl, halo, nitro, hydroxy, COOH, COOR, CONH₂, CONHR, CONR₂,—(CH₂)_(m)—OH wherein m is 0-10, haloalkyl, mono- orpoly-hydroxysubstituted branched alkyl, a carbohydrate group, SO₂OH,SO₂NH₂, SO₂NHR, SO₂NR₂, or OCOR; R is alkyl, alkenyl, alkynyl,alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, aryl heteroaryl ornitro-substituted heteroaryl, or when attached to a nitrogen atom, twoadjacent R groups may combine to form a ring of 5 to 7 members; the R¹and R² are independently C₁₋₅ alkyl; R³ and R⁴ are independently H.

Another preferred embodiment of the present invention includes compoundsof formula (I) wherein X is S, SO, or SO₂; Spacer is —(CH₂)_(n)— or—(CH₂)_(n)—CO—; n is 0-10; Y is phenyl; phenyl which is mono- orpolysubstituted by alkyl, halo, nitro, hydroxy, COOH, COOR, CONH₂,CONHR, CONR₂, —(CH₂)_(m)—OH wherein m is 0-10, haloalkyl, mono- orpoly-hydroxysubstituted branched alkyl, a carbohydrate group, SO₂OH,SO₂NH₂, SO₂NHR, SO₂NR₂, or OCOR; R is alkyl, alkyl-COOH, alkyl-COOalkyl,alkyl-COOaryl, aryl, heteroaryl or nitro-substituted heteroaryl, or whenattached to a nitrogen atom, two adjacent R groups may combine to form aring of 5 to 7 members; the R¹ and R² are independently C₁₋₅ alkyl; R³and R⁴ are independently H.

Another preferred embodiment of the present invention includes compoundsof formula (I) wherein X is S, SO, or SO₂; Spacer is —(CH₂)_(n)— or—(CH₂)_(n)—CO—; n is 0-10; Y is phenyl; phenyl which is mono- orpolysubstituted by alkyl, halo, nitro, hydroxy, COOH, COOR, CONH₂,CONHR, CONR₂, —(CH₂)_(m)—OH wherein m is 0-10, haloalkyl, mono- orpoly-hydroxysubstituted branched alkyl, a carbohydrate group, SO₂OH,SO₂NH₂, SO₂NHR, SO₂NR₂, or OCOR; R is alkyl, alkyl-COOH, alkyl-COOalkyl,alkyl-COOaryl, or nitro-substituted furanyl, or when attached to anitrogen atom, two adjacent R groups may combine to form a ring of 5 to7 members; R¹ and R² are independently C₁₋₅ alkyl; R³ and R⁴ areindependently H.

Another preferred embodiment of the present invention includes compoundsof formula (I) wherein X is S, SO, or SO₂; Spacer is —(CH₂)_(n)— or—(CH₂)_(n)—CO—; n is 0-10; Y is heteroaryl; heteroaryl which is mono- orpolysubstituted by alkyl, alkenyl, alkynyl, CH₂NH₂, CH₂NHR, CH₂NR₂,COOH, COOR, R is alkyl, alkenyl, alkynyl, aryl, alkyl-COOH,alkyl-COOalkyl, alkyl-COOaryl, heteroaryl or nitro substituted orheteroaryl, or when attached to a nitrogen atom, two adjacent R groupsmay combine to form a ring of 5 to 7 members; R¹ and R² areindependently C₁₋₁₅ alkyl; R³ and R⁴ are independently H.

Another preferred embodiment of the present invention includes compoundsof formula (I) wherein X is S, SO, or SO₂; Spacer is —(CH₂)_(n)—; n is0-10, Y is heteroaryl heteroaryl which is mono- or polysubstituted toalkyl, alkenyl, alkynyl, CH₂NH₂, CH₂NHR, CH₂NR₂, COOH, COOR; R is alkyl,alkenyl, alkynyl, aryl, alkyl-COOH; alkyl-COOalkyl, alkyl-COOaryl,heteroaryl, or nitro substituted heteroaryl, or when attached to anitrogen atom, two adjacent R groups may combine to form a ring of 5 to7 members, R¹ and R² are independently C₁₋₅ alkyl; R³ and R⁴ areindependently H.

Another preferred embodiment of the present invention includes compoundsof formula (I) wherein X is S, SO, or SO₂; Spacer is —(CH₂)_(n)—CO—; nis 0-10, Y is heteroaryl; heteroaryl which is mono- or polysubstitutedto alkyl, alkenyl, alkynyl, CH₂NH₂, CH₂NHR, CH₂NR₂, COOH, COOR; R isalkyl, alkenyl, alkynyl, aryl, alkyl-COOH; alkyl-COOalkyl,alkyl-COOaryl, heteroaryl, or nitro substituted heteroaryl, or whenattached to a nitrogen atom, two adjacent R groups may combine to form aring of 5 to 7 members, R¹ and R² are independently C₁₋₅ alkyl; R³ andR⁴ are independently H.

Another preferred embodiment of the present invention includes compoundsof formula (I) wherein X is S, SO, or SO₂; Spacer is —(CH₂)_(n)e— or—(CH₂)_(n)—CO—; n is 0-10, Y is isoxazolyl or furanyl which may beoptionally substituted by mono- or polysubstituted by alkyl, alkenyl,alkynyl, CH₂NH₂, CH₂NHR, CH₂NR₂, COOH, COOR; R is alkyl, alkenyl,alkynyl, aryl, alkyl-COOH; alkyl-COOalkyl, alkyl-COOaryl, heteroaryl, ornitro substituted heteroaryl, or when attached to a nitrogen atom, twoadjacent R groups may combine to form a ring of 5 to 7 members, R¹ andR² are independently C₁₋₅ alkyl, R³ and R⁴ are independently H.

Another preferred embodiment of the present invention includes compoundsof formula (I) wherein X is S, SO, or SO₂; Spacer is —(CH₂)_(n)— or—(CH₂)_(n)—CO—; n is 0-10, Y is isoxazolyl which may be optionallysubstituted by mono- or polysubstituted by alkyl, alkenyl, alkynyl,CH₂NH₂, CH₂NHR, CH₂NR₂, COOH, COOR; R is alkyl alkenyl, alkynyl, aryl,alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, heteroaryl, or nitrosubstituted heteroaryl, or when attached to a nitrogen atom, twoadjacent R groups may combine to form a ring of 5 to 7 members; R¹ andR² are independently C₁₋₅ alkyl; R³ and R⁴ are independently H.

Another preferred embodiment of the present invention includes compoundsof formula (I) wherein X is S, SO, or SO₂; Spacer is —(CH₂)_(n)— or—(CH₂)_(n)—CO—; n is 0-10; Y is furanyl which may be optionallysubstituted by mono- or polysubstituted by alkyl, alkenyl, alkynyl,CH₂NH₂, CH₂NHR, CH₂NR₂, COOH, COOR; R is alkyl, alkenyl, alkynyl, aryl,alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, heteroaryl, or nitrosubstituted heteroaryl, or when attached to a nitrogen atom, twoadjacent R groups may combine to form a ring of 5 to 7 members; R¹ andR² are independently C₁₋₅ alkyl; R³ and R⁴ are independently H.

Another preferred embodiment of the present invention includes compoundsof formula (I) wherein X is S, SO, or SO₂; Spacer is —(CH₂)_(n)— or—(CH₂)_(n)—CO—; n is 0-10; Y is NH₂, NHR or NR₂; R is alkyl, alkenyl,alkynyl, aryl, alkyl-COOH, alkyl-COOalkyl, alkyl-COOaryl, heteroaryl, ornitro substituted heteroaryl, or when attached to a nitrogen atom, twoadjacent R groups may combine to form a ring of 5 to 7 members; R¹ andR² are independently C₁₋₅ alkyl; R³ and R⁴ are independently H.

Another preferred embodiment of the present invention includes compoundsof formula (I) wherein X is S, SO, or SO₂; Spacer is —(CH₂)_(n)— or—(CH₂)_(n)—CO—; n is 0-10; Y is NH₂, NHR or NR₂; R is alkyl, or whenattached to a nitrogen atom, two adjacent R groups may combine to form aring of 5 to 7 members; R¹ and R² are independently C₁₋₅ alkyl; R³ andR⁴ are independently H.

Another preferred embodiment of the present invention includes compoundsof formula (I) wherein X is S, SO, or SO₂; Spacer is —(CH₂)_(n)—; n is0-10; Y is NH₂, NHR or NR₂; R is alkyl, or when attached to a nitrogenatom, two adjacent R groups may combine to form a ring of 5 to 7members; R¹ and R² are independently C₁₋₅ alkyl; R³ and R⁴ areindependently H.

Another preferred embodiment of the present invention includes compoundsof formula (I) wherein X is S, SO, or SO₂; Spacer is —(CH₂)_(n)—; n is0-10; Y is NH₂, NHR or NR₂; R is alkyl, or when attached to a nitrogenatom, two adjacent R groups may combine to form a ring of 5 to 7members; R¹ and R² are independently C₁₋₅ alkyl; R³ and R⁴ areindependently H.

Another preferred embodiment of the present invention includes compoundsof formula (I) wherein X is S, SO, or SO₂; Spacer is —(CH₂)_(n)— or—(CH₂)_(n)—CO—; n is 0-10; Y is selected from the group consisting ofstraight chained, branched or cyclic alkyl; straight chained branched,or cyclic alkyl substituted by OCOR, SO₂OH, COOH or COOR; and OCOR; R isalkyl, alkenyl, alkynyl, and aryl, or when attached to a nitrogen atom,two adjacent R groups may combine to form a ring of 5 to 7 members; R¹and R² are independently C₁₋₅ alkyl; R³ and R⁴ are independently H.

Another preferred embodiment of the present invention includes compoundsof formula (I) wherein X is S, SO, or SO₂; Spacer is —(CH₂)_(n)— or—(CH₂)_(n)—CO—; n is 0-10; Y is selected from the group consisting ofstraight chained, branched or cyclic alkyl; straight chained, branched,or cyclic alkyl substituted by OCOR, SO₂OH, COOH or COOR; and OCOR; R isalkyl or two adjacent R groups may combine to form a ring of 5 to 7members; R¹ and R² are independently C₁₋₅ alkyl; R³ and R⁴ areindependently H.

Another preferred embodiment of the present invention includes compoundsof formula (I) wherein X is S, SO, or SO₂; Spacer is —(CH₂)_(n)—; n is0-10; Y is selected from the group consisting of straight chained,branched or cyclic alkyl; straight chained, branched, or cyclic alkylsubstituted by OCOR, SO₂OH, COOH; or COOR; R is alkyl; R¹ and R² areindependently C₁₋₅ alkyl; R³ and R⁴ are independently H.

Another preferred embodiment of the present invention includes compoundsof formula (I) wherein X is S, SO, or SO₂; Spacer is —(CH₂)_(n)—CO—; nis 0-10; Y is selected from the group consisting of straight chained,branched or cyclic alkyl; straight chained, branched, or cyclic alkylsubstituted by OCOR; R is alkyl; R¹ and R² are independently C₁₋₅ alkyl;R³ and R⁴ are independently H.

Another preferred embodiment of the present invention includes compoundsof formula (I) wherein X is S, SO, or SO₂; Spacer is —(CH₂)_(n)— or—(CH₂)_(n)—CO—; n is 0-10; Y is OCOR; R is alkyl; R¹ and R² areindependently C₁₋₅ alkyl; R³ and R⁴ are independently H.

Another preferred embodiment of the present invention includes compoundsof formula (I) wherein X is S, SO, or SO₂; Spacer is —(CH₂)_(n)—; n is0-10; Y is OCOR; R is alkyl; R¹ and R² are independently C₁₋₅ alkyl; R³and R⁴ are independently H.

Another preferred embodiment of the present invention includes compoundsof formula (I) wherein X is S, SO, or SO₂; Spacer is —(CH₂)_(n)—CO—; nis 0-10; Y is OCOR; R is alkyl; R¹ and R² are independently C₁₋₅ alkyl;R³ and R⁴ are independently H.

Examples of the present invention includes compounds of formula (I)defined as follows:

X═S; R¹═t-butyl; R²═t-butyl; R³═H; R⁴═H, Spacer═—CH₂—;Y═4-carboxymethylphenyl;

X═S; R¹═t-butyl; R²═t-butyl; R³═H; R⁴═H; Spacer═—CH₂—; Y═4-nitrophenyl;

X═S; R¹═t-butyl; R²═t-butyl; R³═H; R⁴═H; Spacer═—(CH₂)₂—;Y═4-nitrophenyl;

X═S; R¹═t-butyl; R²═t-butyl; R³═H; R⁴═H; Spacer═—CH₂—; Y═2-carboxyethyl;

X═S; R¹═t-butyl; R²═t-butyl; R³═H; R⁴═H; Spacer═—CH₂—;Y═3,5-di-b-butyl-4-carboypropanoyloxy;

X═S; R¹═t-butyl; R²═t-butyl; R³═H; R⁴═H; Spacer═—CH₂—;Y═4-carboxyphenyl;

X═S; R¹═t-butyl; R²═t-butyl; R³═H; R⁴═H; Spacer═—CH₂—;Y═1-acetyloxy-1-methylethyl;

X═S; R¹═t-butyl; R²═t-butyl; R³═H; R⁴═H; Spacer═—CH₂—; Y═3-nitrophenyl;

X═S; R¹═t-butyl; R²═t-butyl; R³═H; R⁴═H; Spacer═—CH₂—;Y═2,4-dinitrophenyl;

X═S; R¹═t-butyl; R²═t-butyl; R³═H; R⁴═H; Spacer═—CH₂—;Y═4-trifluoromethylphenyl;

X═S; R¹═t-butyl; R²═t-butyl; R³═H; R⁴═H; Spacer═—CH₂—;Y═2-carboxyfuranyl;

X═S; R¹═t-butyl; R²═t-butyl; R³═H; R⁴═H; Spacer═—CH₂—;Y═4-(N,N-dimethyl)sulfonamidophenyl;

X═S; R¹═t-butyl; R²═t-butyl; R³═H; R⁴═H; Spacer═—CH₂—; Y═4-nitrophenyl;

X═S; R¹═t-butyl; R²═t-butyl; R³═H; R⁴═H; Spacer═—CH₂—; Y═4-nitrophenyl;

X═S; R¹═t-butyl; R²═t-butyl; R³═H; R⁴═H; Spacer═—CH₂—;Y═4-acetyloxyphenyl;

X═S; R¹═t-butyl; R²═t-butyl; R³═H; R⁴═H; Spacer═—CH₂—; Y═4-methylphenyl;

X═S; R¹═t-butyl; R²═t-butyl; R³═H; R⁴═H; Spacer═—CH₂—; Y═4-fluorophenyl;

X═S; R¹═t-butyl; R²═t-butyl; R³═H; R⁴═H; Spacer═—CH₂—; Y═ethylsulfonicacid;

X═S; R¹═t-butyl; R²═t-butyl; R³═H; R⁴═H; Spacer═—CH₂—;Y═2-dimethylaminomethyl;

X═S; R¹═t-butyl; R²═t-butyl; R³═H; R⁴═H; Spacer═—(CH₂)₃—;Y═dimethylamino;

X═S; R¹═t-butyl; R²═t-butyl; R³═H; R⁴═H; Spacer═—(CH₂)₅—; Y═acetyloxy;

X═S; R¹═t-butyl; R²═t-butyl; R³═H; R⁴═H; Spacer═—CH₂—;Y═4-(2-hydroxy)ethylphenyl.

In another embodiment of the invention, there is provided a compound offormula (II) and a method for treating a disease mediated by theexpression of VCAM-1 comprising administering an effective amount of acompound of formula (II):

wherein

R_(a), R_(b), R_(c), and R_(d) are independently hydrogen, straightchained, branched (for example, tert-butyl), or cyclic alkyl which maybe substituted, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, alkaryl, substituted alkaryl, aralkyl or substitutedaralkyl; substituents on the R_(a), R_(b), R_(c) and R_(d) groups areselected from the group consisting of hydrogen, halogen, alkyl, nitro,amino, haloalkyl, alkylamino, dialkylamino, acyl, and acyloxy;

Z is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,aralkyl, alkaryl, heteroaryl, heteroaralkyl, a carbohydrate group,—(CH₂)—R_(e), —C(O)—R_(g), and —C(O)—(CH₂)_(n)—R_(h), wherein (a) wheneach of R_(a), R_(b), R_(c), and R_(d) are t-butyl, Z cannot be hydrogenand (b) when each of R_(a), R_(b), R_(c), and R_(d) are t-butyl, Zcannot be the residue of succinic acid;

R_(e) is selected from the group consisting of alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy,substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, NH₂, NHR, NR₂,mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, acyloxy, substituted acyloxy, COOH,COOR, —CH(OH)R_(k), hydroxy, C(O)NH₂, C(O)NHR, C(O)NR₂;

R_(g) is selected from the group consisting of alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy,substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, NH₂, NHR, NR₂,mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl;

R_(h) is selected from the group consisting of alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy,substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, NH₂, NHR, NR₂,mono- or polyhydroxy-substituted alkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, acyloxy, substituted acyloxy, COOH,COOR, —CH(OH)R_(k), hydroxy, O-phosphate, C(O)NH₂, C(O)NHR, C(O)NR₂ andpharmaceutically acceptable salts thereof;

or, in an alternative embodiment R_(e), R_(g) and R_(h) canindependently be a substituent which improves the water solubility ofthe compound, including, but not limited to C(O)-spacer-SO₃H, whereinspacer is as defined above, C(O)-spacer-SO₃M, wherein M is a metal usedto form a pharmaceutically acceptable salt, for example, sodiumC(O)-spacer-PO₃H₂, C(O)-spacer-PO₃M₂, C(O)-spacer-PO₃HM,C(O)-spacer-PO₄H, C(O)-spacer-PO₄M, SO₃M, —PO₃H₂, —PO₃M₂, —PO₃HM, cyclicphosphates, polyhydroxyalky, carbohydrate groups, C(O)-spacer-[O(C₁₋₃alkyl)_(p)]_(n), wherein n is as defined above and p is 1, 2, or 3,—[O(C₁₋₃ alkyl)_(p)]_(n), carboxy lower alkyl, lower alkycarbonyl loweralkyl, N,N-dialkylamino lower alkyl, pyridyl lower alkyl, imidazolyllower alkyl, morpholinyl lower alkyl, pyrrolidinyl lower alkyl,thiazolinyl lower alkyl, piperidinyl lower alkyl, morpholinyl lowerhydroxyalkyl, N-pyrryl, piperizinyl lower alkyl, N-alkyl piperazinyllower alkyl, triazolyl lower alkyl, tetrazolyl lower alkyl,tetrazolylamino lower alkyl, or thiazolyl lower alkyl.

Substituents on the groups defined above are selected from the groupconsisting of alkyl, alkenyl, alkynyl, hydroxy, halo, nitro, amino,alkylamino, dialkylamino, carboxy, aryl, heteroaryl, COOR, CONH₂, CONHR,CONR₂, haloalkyl, alkoxyalkyl, mono- or polyhydroxyalkyl, CH₂—OR,CH₂—OH, OCOR, O-phosphate, SO₂—NH₂, SO₂—NHR, SO₂—NR₂.

A preferred embodiment of the present invention includes compounds offormula (II) wherein R_(a), R_(b), R_(c), and R_(d) are independently orstraight chained, branched, or cyclic C₁₋₁₀ alkyl; Z is selected fromthe group consisting of hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, a carbohydrate group,—(CH₂)—R_(e), —C(O)—R_(g), and —C(O)—(CH₂)_(n)—R_(h), andpharmaceutically acceptable salts thereof.

Another preferred embodiment of the present invention includes compoundsof formula (II) wherein R_(a), R_(b), R_(c), and R_(d) are independentlyhydrogen or straight chained, branched, or cyclic C₁₋₅ alkyl; Z isselected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acarbohydrate group, —(CH₂)—R_(e), —C(O)—(CH₂)_(n)—R_(h), andpharmaceutically acceptable salts thereof.

Another preferred embodiment of the present invention includes compoundsof formula (II) wherein R_(a), R_(b), R_(c), and R_(d) are independentlyhydrogen or straight chained, branched, or cyclic C₁₋₅ alkyl; Z isselected from the group consisting of hydrogen, alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, —CH₂-aryl substitutedalkynyl, a carbohydrate group, —CH₂—NR₂, —CH₂-alkoxy, —CH₂—CHOH,—CH₂-substituted aryl, —CH₂-alkyl, —CH₂-substituted alkyl, —CH₂,—OCO-alkyl, —CH₂—OCO-substituted alkyl, —CH₂—COOR,—CH₂—CH(OH)CH₂NHCH₂COOR, —CH₂—CH(OH)-substituted oxiranyl (wherein thesubstituent is selected from the group consisting of hydrogen, CH₂OH,CH₂OCHOH-oxiranyl), —CO-aryl, —CO-substituted aryl, —CO-heteroaryl,—CO-substituted heteroaryl, —CO—(CH₂)_(n)—COOR, —CO—(CH₂)_(n)—OH,—CO—(CH₂)_(n)—O-phosphate, —CO—(CH₂)_(n)—CO—NR₂, —CO—(CH₂)_(n)-aryl,—CO—(CH₂)_(n)-substituted aryl, —CO—(CH₂)_(n)-heteroaryl,—CO—(CH₂)_(n)-substituted heteroaryl, —CO—(CH₂)_(n)—CONH(CH₂)COOR,—CO—(CH₂)_(n)—CON((CH₂)COOR)₂, monosaccharides, and cyclicmonosaccharides, and pharmaceutically acceptable salts thereof.

Another preferred embodiment of the present invention includes compoundsof formula (II) wherein R_(a), R_(b), R_(c), and R_(d) are independentlyhydrogen or straight chained, branched, or cyclic C₁₋₅ alkyl; Z isselected from the group consisting of hydrogen, alkyl, hydroxy alkyl,polyhydroxy alkyl, alkenyl, hydroxy alkenyl, acyl-substituted alkenyl,alkoxy alkyl, nitrophenylalkyl, aminophenylalkyl, alkylaminophenylalkyl,dialkylaminophenylalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,carboxyalkyl, acyloxyalkyl, oxiranyl-substituted hydroxyalkyl,hydroxyalkyl-substituted oxiranylmethylene, oxiranyl-substitutedhydroxyalkoxyalkyl oxiranylmethylene, oxiranylmethylene,carboxyalkylaminohydroxyalkyl, alkoxyhydroxyalkyl, glucopyranosyl,galactopyranosyl, N,N-diacylalkylaminohydroxyalkyl,carboxyalkylaminopolyhydroxyalkyl,(amino)(carboxy)alkylaminohydroxyalkyl, acyloxyhydroxyalkyl,polyhydroxyalkylaminohydroxyalkyl, CO-carboxyalkyl, CO-nitrofuranyl,CO-hydroxyalkyl, CO-polyhydroxyalkyl, CO-amidoalkyl, CO-aminoalkyl,CO-alkylaminoalkyl, CO-dialkylaminoalkyl, CO-acylalkyl,CO-alkoxycarbonylalkyl, CO-tetrazolylalkyl, CO-(acyl)(amino)alkylamino,dialkoxycarbonylalkylamidoalkyl, CO-hydroxyphenyloxyphosphonoxyalkyl, orpharmaceutically acceptable salts thereof.

Examples of the present invention include compounds of formula (II)wherein:

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═4-nitrophenyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═CO—(CH₂)₂—COOH;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═CO—(5-nitrofuran-2-yl);

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═3-carboxypropyl;

R_(a)═1-methylethyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═4-aminobutyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═4-aminobutyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═3-hydroxypropanoyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═t-butylcarbonyloxymethyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═H; and R_(d)═H; Z═4-aminobutyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═H; and R_(d)═H; Z═3-carboxypropyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═carboxymethyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═2-(CONH₂)ethanoyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═CO-aminomethyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═CO-(2-carboxyethyl);

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═CO—(2-methoxycarbonylethyl);

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═CO-aminomethyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═CO-3-carboxypropyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═3-carboxypropyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═CO-2-carboxyethyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═CO-ammonium methyl (chloride)

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═2-hydroxy-2-oxiranyl-ethyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═3-hydroxymethyloxirany-2-ylmethyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═3-(2-hydroxy-2-oxiranyl)ethoxyoxiran-2-ylmethyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═oxiranylmethyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═2-hydroxy-3-carboxymethylaminopropyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═2,3,4-trihydroxybutyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═2-hydroxy-3-ethoxypropyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═2,3-dihydroxypropyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl; Z═ethyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═2-ethoxycarbonylethenyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═4-N,N-dimethylaminophenethyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═CO-2-carboxyethyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═CO-2-carboxyethyl (L-arginine ester);

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═methoxycarbonylpropyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═2-carboxyethenyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═galactopyranosylmethyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═3-(N,N-diethylamino)propyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═ethoxycarbonylethenyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═carboxymethylaminocarbonylmethyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═1,3-dicarboxypropylaminocarbonylmethyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═2-hydroxy-3-(1,3-diethoxycarbonyl)propylaminopropyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═2,3-dihydroxy-4-carboxymethylaminobutyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═2-hydroxy-3-(5-amino-5-carboxy)propylaminopropyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═4-ethylcarbonyloxybutyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═4-hydroxybutyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═glucopyranosylmethyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═CO-3-tetrazolylpropyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═3-hydroxypropenyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═CH₂CONH—(CH₂)CH(NH₂)COOH;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═CH₂CONHCH(COOet)CH₂CH₂(COOet);

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═glucopyranosylmethyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═2,3,4,5,6-pentahydroxyhexane;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═CO-3-(2-hydroxyphenyloxyphosphoxy)propyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═CO-2,2-dimethyl-3-hydroxypropyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═2-hydroxy-3-acetoxypropyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═2-acetoxy-3-hydroxypropyl;

R_(a)═t-butyl, R_(b)═t-butyl, R_(c)═t-butyl, and R_(d)═t-butyl;Z═CH₂CH(OH)CH₂NH(2,3,4,5,6-pentahydroxyhexane.

The compounds of formula (I) can be prepared by utilizing knownprocedures and techniques, or routine modifications thereof. A generalsynthetic scheme for preparing compounds of formula (I) is set forth inScheme A, wherein all substituents, unless otherwise indicated, arepreviously defined.

Scheme A

The synthesis of the starting thiol, 4-mercapto-2,6-di-t-butylphenol, isdescribed in the literature (U.S. Pat. No. 3,129,262 to Laufer,incorporated herein by reference in its entirety). The starting alkylhalides are commercially available or made from commercially availablestarting materials by methods known to one of ordinary skill in the art.

A quantity of the 4-mercapto-2,6-di-t-butylphenol is dissolved inethanol to make a 0.5 M solution and treated with 1.2 equivalents ofsodium hydroxide (5 N aqueous solution). After 5 minutes 1.2 equivalentsof alkyl halide is added and the reaction mixture stirred at roomtemperature for 24 hours. The reaction is quenched with 1 N HCl to pH 7,diluted with water, extracted with ether and dried over magnesiumsulfate. The product is purified by silica gel chromatography.

Starting materials for use in the general synthetic procedure outlinedin Scheme A are readily available to one of ordinary skill in the art.For example, certain phenol starting materials for various compounds offormula (I), such as 2,6-di-tertiarybutyl-4-mercaptophenol, aredescribed in U.S. Pat. No. 3,576,883, U.S. Pat. No. 3,952,064, U.S. Pat.No. 3,479,407 and in Japanese Patent Application 73-28425.

In general, a phenol of structure (I) can be prepared by dissolving theappropriate 2,6-dialkyl-4-thiophenol (or suitably protected derivatives)in alcohol, preferably in ethanol, followed by addition of a halogenatedaryl compound.

The starting material, a 2,6-dialkyl-substituted thiophenol, may beprotected by any of the many protecting groups known to one of ordinaryskill in the art. Examples of suitable phenol protecting groups areethers, such as methoxymethyl, 2-methoxyethoxymethyl, tetrahydropyranyl,t-butyl and benzyl; silyl ethers, such as trimethylsilyl and1-butyldimethylsilyl; esters, such as acetate and benzoate; carbonates,such as methylcarbonate and benzyl carbonate; as well as sulfonates,such as methane sulfonate and toluene sulfonate.

The following examples present typical syntheses as described in SchemeA. These examples are understood to be illustrative only and are notintended to limit the scope of the present invention in any way. As usedherein, the following means have the indicated meanings “g” refers tograms; “mmol” refers to millimoles; “mL” refers to milliliters; “bp”refers to boiling point; “C” refers to degrees Celsius; “mm Hg” refersto millimeters of mercury; “mp” refers to melting point; “mg” refers tomilligrams; “μM” refers to micromolar; “μg” refers to micrograms.

EXAMPLE 1 2,6-di-tert-butyl-4-thio(4′(methyl)phenylacetic acid))phenol

Reaction Description

2,6-di-t-butyl-4-thiophenol (238 mg, 1 mmol) was dissolved in ethanol(0.7 mL) and cooled to 0° C. 5 N NaOH (0.6 mL, 3 mmol) was addedfollowed by addition of 4-(bromomethyl)phenyl acetic acid (229 mg, 1mmol). The reaction was warmed to room temperature and after 0.5 h thereaction was complete. The reaction was quenched with 1 N HCl (3.5 mL)and diluted with ether (25 mL). The ether layer was separated and washedwith water (1×5 mL) and brine (1×5 mL), dried over MgSO₄, filtered andconcentrated. Chromatography over silica gel and eluting with 50:50ether/hexane provided 170 mg of(2,6-di-tert-butyl-4-thio(4′(methyl)phenylacetic acid))phenol). ¹H NMR(CDCl₃, 400 MHz): δ 7.24 (s, 2 H), 7.17 (d, J=8.4 Hz, 2 H), 7.11 (d,J=8.4 Hz, 2 H), 5.20 (s, 1 H), 3.91 (s, 2 H), 3.59 (s, 2 H), 1.33 (s, 18H).

EXAMPLE 2 2,6-di-tert-butyl-4-thio(4′-nitrobenzyl)phenol

Reaction Description

A solution of 0.28 mmol (68 mg) of 2,6-di-tert-butyl-4-thiophenol in 0.5mL of EtOH (denatured) was stirred and treated with 0.3 mmol (0.06 mL)of NaOH (5 N in de-ionized water) at 0° C. After stirring for 5 min,0.29 mmol (62 mg) of 4-nitrobenzyl bromide was added to given an orangesolution. The progress of the reaction was monitored by TLC (1:1hexanes-hexanes-CH₂Cl₂; visualized by UV and PMA/char). The bromide wasconsumed over a 2 h period. The mixture was then quenched with sat.NaCl-EtOAc. The aqueous layer was back-extracted with 2×2 mL of EtOAc;the combined organic layers were dried over anhydrous MgSO₄. The dryingagent was removed by filtration; solvent was removed by rotaryevaporation to give a crude oil. The oil was purified by preparativethin-layer chromatography (pTLC) using 2×500μ plates and 1:1hexanes-CH₂Cl₂ as eluant. The desired product(2,6-di-tert-butyl-4-thio(4′-nitrobenzyl)phenol) was obtained in 86%yield (90 mg). ¹H NMR (CDCl₃, 400 MHz): δ 8.10 (d, J=8.8 Hz, 2 H), 7.25(d, J=8.8 Hz, 2 H), 7.04 (s, 2 H), 5.28 (s, 1 H), 3.98 (s, 2 H), 1.34(H).

EXAMPLE 3 2,6-di-tert-butyl-4-thio(4′-nitrophenethyl)phenol

Reaction Description

0.48 mmol (115 mg) of 2,6-di-tert-butyl-4-thiophenol was taken up andstirred in 2 mL of dry THF. The mixture was treated with 0.67 mmol (27mg) of sodium hydride (60% suspension in mineral oil) to give a clear,dark yellow solution. 4-Nitrophenethyl iodide (0.49 mmol; 135 mg) wasadded to give a dark brown mixture which was stirred overnight. Theprogress of the reaction was monitored by TLC (3×10:1 hexanes-CH₂Cl₂;visualized by UV and PMA/char), and the reaction was quenched (with sat.NaCl-EtOAc) when only traces of the starting iodide remained. Theaqueous layer was back-extracted with 2×5 mL of EtOAc; the combinedorganic layers were dried over anhydrous MgSO₄. Filtration to remove thedrying agent followed by solvent removal by rotary evaporation gave adark brown oil. Purification of the crude material using radialchromatography (10:1 hexanes-CH₂Cl₂; 4 mm plate) gave 93 mg (50% yield)of 2,6-di-tert-butyl-4-thio(4′-nitrophenethyl)phenol. ¹H NMR (CDCl₃, 400MHZ): δ 8.15 (d, J=8.8 Hz, 2 H), 7.34 (d, J=8.4 Hz, 2 H), 7.24 (s, 2 H),5.26 (s, 1 H), 3.11 (t, J=7.2 Hz, 2 H), 3.09 (t, J=7.6 Hz, 2 H), 1.43(s, 18 H).

EXAMPLE 4 2,6-di-tert-butyl-4-thio(3′-nitrobenzyl)phenol

Reaction Description

3-Nitrobenzyl chloride (0.42 mmol; 72 mg) and2,6-di-tert-butylthiophenol (0.42 mmol; 100 mg) were dissolved in 0.7 mLof EtOH and treated with 92 μL of NaOH (5 N solution). The reactionmixture was stirred for 19.5 h then quenched with sat. NaCl andextracted with EtOAc. The aqueous layer was back-extracted with EtOAc(2×10 mL). The organic portions were collected, dried over Na₂SO₄, andconcentrated in to a yellow oil. The crude material was placed undervacuum for 2 h. Purification was performed via radial chromatographyusing 2 mm (SiO₂) plates and 4:1 hexanes-EtOAc.2,6-di-tert-butyl-4-thio(3′-nitrobenzyl)phenol was obtained as a yellowoil (108 mg; 69% yield). 8.07 (app d, J=7.6 Hz, 1 H), 7.87 (s, 1 H),7.48 (AB d, J=7.6 Hz, 1 H), 7.42 (AB m, J=7.6, 8.0 Hz, 1 H), 7.05 (s, 2H), 5.27 (s, 1 H), 3.99 (s, 2 H), 1.34 (s, 18 H).

EXAMPLE 5 2,6-di-tert-butyl-4-thio(2′,4′-dinitrobenzyl)phenol

Reaction Direction

2,4-dinitrobenzyl chloride (0.42 mmol; 91 mg) and2,6-di-tert-butylthiophenol (0.42 mmol; 100 mg) were dissolved in 0.7 mLof EtOH and treated with 92 μL of NaOH (5 N solution). The reactionmixture was stirred for 19.5 h then quenched with sat. NaCl andextracted with EtOAc (25 mL). The aqueous layer was back-extracted withEtOAc (2×10 mL). The organic layers were collected, dried over Na₂SO₄,and concentrated to a brown oil. Purification of the oil via radialchromatography using 2 mm plate (SiO₂) and 4:1 hexanes-EtOAc as eluantgave 2,6-di-tert-butyl-4-thio(2′,4′-dinitrobenzyl)phenol as a yellow oil(37 mg, 21% yield). ¹H NMR (CDCl₃, 400 MHZ): δ 8.74 (app d, J=2.4 Hz, 1H), 8.24 (dd, J=8.8 2.4 Hz, 1 H), 7.29 (d, J=8.8 Hz, 1 H), 6.98 (s, 2H), 5.35 (s, 1 H), 4.36 (s, 2 H), 1.34 (s, 18 H).

EXAMPLE 6 (2,6-di-tert-butyl-4-thio(4′-(trifluoromethyl)benzyl)phenol

Reaction Description

4-(Trifluoromethyl)benzyl bromide (0.42 mmol; 100 mg) and2,6-di-tert-butylthiophenol (0.42 mmol; 100 mg) were dissolved in 0.7 mLof EtOH and treated with 92 μL of NaOH (5 N solution). The reactionmixture turned brown within 30 min, and precipitation was observed. Themixture was stirred for 22 h then quenched with sat. NaCl and EtOAc. Theaqueous layer were back-extracted with 2×10 mL of EtOAc. The combinedorganic layers were dried over Na₂SO₄ then concentrated to give abrownish orange solid. Purification of the solid via radialchromatography using 4 mm plate (SiO₂) and 4:1 hexanes-EtOAc as eluantgave (2,6-di-tert-butyl-4-thio(4′-(trifluoromethyl)benzyl)phenol as ayellow solid (140 mg; 84% yield). ¹H NMR (CDCl₃, 400 MHZ): δ 7.48 (AB d,J=8.0 Hz, 2 H), 7.20 (AB d, J=8.0 Hz, 2 H), 7.01 (s, 2 H), 5.24 (s, 1H), 3.93 (s, 2 H), 1.33 (s, 18 H).

EXAMPLE 7 2,6-di-tert-butyl-4-thio(2′-furancarboxylicacid)-5-methyl)phenol

Reaction Description

2,6-di-tert-butyl-4-thiophenol (0.49 mmol; 116 mg) was dissolved in dryTHF (2 mL), stirred, and treated with sodium hydride (0.58 mmol; 23 mg;60% dispersion in mineral oil). The resulting yellow solution wastreated with methyl 5-(chloromethy)-2-furoate (0.54 mmol; 95 mg). Thebrown mixture was stirred for 22 h then quenched with brine. Extractionwith EtOAc (3×3 mL), combination of the organic layers and drying overMgSO₄ then solvent removal by rotary evaporation gave a crude oil. Thecrude product was eluted on 2×500μ preparative thin-layer chromatographyplates (SiO₂; 1:1 hexanes-CH₂Cl₂ as eluant) to give the expectedintermediate (132 mg; 72% yield). The intermediate (0.35 mmol; 132 mg)was taken up in 4:1:1 MeOH-THF-H₂O (3 mL), stirred, and treated withLiOH monohydrate (1.2 mmol; 50 mg). The mixture was stirred at roomtemperature for 18 h then solvent was removed to give2,6-di-tert-butyl-4-thio((2′-furancarboxylic acid)-5-methyl)phenol (94mg; 74% yield) as a tan solid. ¹H NMR (CDCl₃, 400 MHZ): δ 7.21 (d, J=3.2Hz, 1 H), 7.19 (s, 2 H), 6.17 (d, J=3.2 Hz, 1 H), 530 (br s, 1 H), 4.00(s, 2 H), 1.40 (s, 18 H).

EXAMPLE 82,6-di-tert-butyl-4-thio(4′-methyl-N,N′-dimethylbenzenesulfonamide)phenol

Reaction Description

2,6 di-t-butyl-4-thiophenol (180 mg, 0.755 mmol) was dissolved inethanol (1.5 mL) and then treated with 5 N NaOH (0.15 mL, 0.75 mmol).After 5 min, 4-(N,N-dimethylsulfonamide)benzyl bromide (210 mg, 0.755)in ethanol (1.5 mL) was added to the reaction. The resulting mixture wasstirred at room temperature for 3 h. The reaction was quenched with 1NHCl to pH 7, diluted with water (3 mL), extracted with ether (10 mL),separated and dried over MgSO₄. The crude reaction mixture was purifiedby column chromatography over silica gel and eluting with 30:70ether/hexane followed by 40:60 ether/hexane. The appropriate fractionswere collected to give 160 mg of the desired product. ¹H NMR (CDCl₃, 400MHz): δ 7.67 (d, J=8.4 Hz, 2 H), 7.32 (d, J=8.4 Hz, 2 H), 7.08 (s, 2 H),5.27 (s, 1 H), 2.69 (s, 6 H), 1.36 (s, 18 H).

EXAMPLE 9 2,6-di-tert-butyl-4-sulfinyl(4′-nitrobenzyl)phenol

Reaction Description

2,6-di-tert-butyl-4-thio(3′-nitrobenzyl)phenol (157 mg, 0.42 mmol) wastaken up in methylene chloride (4.2 mL) and mCPBA was added. After 15min the reaction was diluted with ether (15 mL) and washed withsaturated aqueous sodium bicarbonate (2×5 mL), followed by water (1×5mL) and brine (1×5 mL). The ether layer was dried over MgSO₄, filtered,and concentrated. The resulting oil was chromatographed by radial silicagel chrolmatography eluting with a concentration gradient of 30:70ether/hexane to 80:20 ether/hexane. The appropriate fractions werecollected (Rf=0.2, 80:20 ether/hexane) and concentrated to give 50 mg of2,6-di-tert-butyl-4-thio(3′-nitrobenzyl)phenol sulfoxide. ¹H NMR (CDCl₃,400 MHz): δ 8.11 (d, J=8.8 Hz, 2 H), 7.07 (br s, 4 H), 5.57 (br s, 1 H),4.13 (d, J=12.4 Hz, 2 H), 4.01 (d, J=12.4 Hz, 2 H), 1.36 (s, 18 H).

EXAMPLE 10 2,6-di-tert-butyl-4-(sulfonyl-(4′-nitrobenzyl))phenol

Reaction Description

2,6-di-tert-butyl-4-thio(3′-nitrobenzyl)phenol (157 mg, 0.42 mmol) wastaken up in methylene chloride (4.2 mL) and mCPBA was added. After 15minutes, the reaction was diluted with ether (15 mL) and washed withsaturated aqueous sodium bicarbonate (2×5 mL), followed by water (1×5mL) and brine (1×5 mL). The ether layer was dried over MgSO₄, filtered,and concentrated. The resulting oil was chromatographed by radial silicagel chromatography eluting with a concentration gradient of 30:70ether/hexane to 80:20 ether/hexane. The appropriate fractions werecollected (Rf=0.5, 80:20 ether/hexane) and concentrated to give 72 mg ofproduct. 8.16 (d, J=8.4 Hz, 2 H), 7.38 (s, 2 H), 7.29 (d, J=8.4 Hz, 2H), 5,84 (s, 1 H), 4.35 (s, 18 H).

EXAMPLE 11 2,6-di-tert-butyl-4-thio(4′-acetoxybenzyl)phenol

Reaction Description

A solution of 2,6-di-tert-butylthiophenol (0.46 mmol; 110 mg) in dry DMF(4.2 mL) was treated with sodium hydride (0.63 mmol; 25 mg; 60%dispersion in mineral oil) and allowed to stir at room temperature for15 min. The orange mixture was treated with 4-(chloromethyl)phenylacetate (0.42 mmol; 77 mg) resulting in a rust-brown color. The mixturewas stirred for 6.5 h then diluted with EtOAc (20 mL) and washed withde-ionized H₂O (25 mL). The organic layer was washed with sat. NaCl thenconcentrated to give a crude oil. Purification by column chromatography(SiO₂) using 4:1 hexanes-EtOAc gave2,6-tert-butyl-4-thio(4′-acetoxybenzyl)phenol as an oil (38 mg; 21%yield). ¹H NMR (CDCl₃, 400 MHz): δ 7.17 (AB d, J=8.8 Hz, 2 H), 7.10 (s,2 H), 6.97 (AB d, J=8.8 Hz, 2 H), 5.23 (s, 1 H), 3.94 (s, 2 H), 2.29 (s,3 H), 1.37 (s, 18 H).

EXAMPLE 12 2,6-di-tert-butyl-4-thio(4′-methylbenzyl)phenol

Reaction Description

A solution of 0.64 mmol (153 mg) of 2,6-di-tert-butylthiophenol in 1.6mL of dry THF was stirred and treated with 0.85 mmol (34 mg) of sodiumhydride (60% suspension in mineral oil) to give a dark orange-brownmixture. 4-Methylbenzyl bromide (0.66 mmol; 122 mg) was added. Themixture was stirred overnight. The progress of the reaction wasmonitored by TLC (hexanes; visualization by UV and PMA/char). Afterapprox. 24 h, the appearance of product was detected by TLC (PMAstaining gave a blue-black spot). The reaction was quenched using sat.NaCl-EtOAc. The aqueous layer was back-extracted with 2×5 mL of EtOAc;the combined organic layers were dried over anhydrous MgSO₄ thenfiltered to remove the drying agent. Removal of solvent by rotaryevaporation gave a crude oil that was eluted twice on 2×500μ preparativeTLC (SiO₂) plates using hexanes. The product(2,6-di-tert-butyl-4-thio(4′-methylbenzyl)phenol) was isolated as ayellow solid in 32% yield (70 mg). ¹H NMR (CDCl₃, 400 MHz): δ 7.10 (s, 2H), 7.07 (s, 4 H), 5.22 (s, 1 H), 3.94 (s, 2 H), 2.33 (s, 3 H), 1.38 (s,18 H).

EXAMPLE 13 2,6-di-tert-butyl-4-thio(4′-fluorobenzyl)phenol

Reaction Description

A solution of 2,6-di-tert-butylthiophenol (0.46 mmol; 110 mg) in 0.7 mLof EtOH was treated with 92 μL of NaOH (5 N solution). The brown mixturewas then treated with 4-fluorobenzyl bromide (0.42 mmol; 52 μL) thenstirred for 24 h. The mixture was quenched with sat. NaCl and extractedwith EtOAc (20 mL). The aqueous layer was back extracted with 2×10 mL ofEtOAc. The combined organic layers were dried over Na₂SO₄ thenconcentrated to give the crude product. Purification by MPLC (SiO₂)using a solvent gradient of 100% hexanes to 19:1 hexanes-EtOAc gave 119mg of product that was contaminated with starting thiol. Furtherpurification via preparative thin-layer chromatography (pTLC) using2×500μ SiO₂ plates and 19:1 hexanes-EtOAc as eluant gave2,6-di-tert-butyl-4-thio(4′-fluorobenzyl)phenol (34 mg; 34% yield). ¹HNMR (CDCl₃, 400 MHz): δ 7.09 (AB t, J=8.8 Hz, 2 H), 7.07 (s, 2 H), 6.92(AB t, J=8.8 H, 2 H), 5.23 (s, 1 H), 3.91 (s, 2 H), 1.36 (s, 18 H).

EXAMPLE 14 2,6-di-tert-butyl-4-thio(3′-propanesulfonic acid)phenol

Reaction Description

2,6-di-tert-butylthiophenol (0.84 mmol; 200 mg) and3-bromopropanesulfonic acid (0.92 mmol; 207 mg) were taken up in EtOHand treated with 0.18 mL of NaOH (5 N solution). The reaction wasallowed to stir for 90 h then quenched with 1 mL of 0.3 N HCl andextracted with 10 mL of EtOAc. The organic layer was dried over MgSO₄,concentrated on SiO₂ (rotary evaporation), and purified via MPLC usingthe following solvent gradient: 100% CH₂Cl₂ followed by 4:1 CH₂Cl₂-MeOH(100 mL) followed by 4:1 CH₂Cl₂-MeOH containing 0.4 mL AcOH.2,6-di-tert-butyl-thio(3′-propanesulfonic acid)phenol was obtained as anoff-white solid (126 mg; 42% yield). ¹H NMR ((CD₃)₂SO, 400 MHz): δ 7.06(s, 2 H), 2.88 (app t, J=7.2, 7.6 Hz, 2 H), 2.52-2.48 (m, 2 H), 1.88 (s,2 H), 1.80 (pent, J=7.2, 7.6 Hz, 2 H), 1.35 (s, 18 H). LRMS: Neg. Ion ES359 (M—H).

EXAMPLE 152,6-di-tert-butyl-4-thio(5′-methyl-2′-((dimethylamino)methyl)furan)phenol

Reaction Description

A solution of 2,6-di-tert-butyl-4-thiophenol disulfide (0.24 mmol; 112mg) and 2-((dimethylamino)methyl)-5-(hydroxymethyl)furan (0.13 mmol; 25mg) in 2.4 mL of dry THF was treated with 0.13 mmol (32 mg) oftributylphosphine. The reaction was stirred for over 60 h then solventwas removed by rotary evaporation to give a light yellow oil. The crudeoil was purified by radial chromatography (2 mm SiO₂ plate; 95:5CH₂Cl₂-MeOH as eluant) to give 7.3 mg (7.5% yield) of the title compoundas a light yellow amorphous solid. ¹H NMR (CDCl₃, 400 MHz): δ 7.17 (s, 2H), 6.22 (d, J=3.2 Hz, 1 H), 5.97 (d, J=3.2 Hz, 1 H), 5.22 (br s H),3.95 (s, 2 H), 3.72 (s, 2 H), 2.37 (s, 6 H), 1.40 (s, 18 H).

EXAMPLE 16 2,6-di-tert-butyl-4-thio(3′-(dimethylamino)propyl))phenol

Reaction Description

A solution of 0.5 mmol (119 mg) of 2,6-di-tert-butylthiophenol in 1.5 mLof dry DMF was stirred and treated with 0.55 mmol (22 mg) of sodiumhydride (60% dispersion in mineral oil). 3-(Dimethylamino)propylchloride hydrochloride (0.5 mmol; 79 mg) was added, and the brownmixture was stirred for 2 days. TLC (1:1 hexanes-CH₂Cl₂; visualizationby UV and PMA/char) showed mostly starting materials. The mixture wastreated with 0.5 mmol NaOH (5 N solution) then stirred overnight. TLCanalysis showed the appearance of a new UV-active material (low Rf;streaks). The reaction was quenched with sat. NaCl-EtOAc. The aqueouslayer was back-extracted with EtOAc, and the combined organic layerswere dried over anhydrous MgSO₄. Drying agent was removed by filtration.Solvent removal by rotary evaporation gave a brown oil. Purification bypreparative thin-layer chromatography (pTLC) using 2×500μ plates (SiO₂)and EtOH as eluant provided2,6-di-tert-butyl-4-thio(3′-(dimethylamino)propyl))phenol as a paleyellow solid (61 mg; 37% yield) ¹H NMR (CDCl₃, 400 MHz): δ 7.24 (s, 2H), 5.20 (s, 1 H), 2.85 (t, J=7.6, 7.2 Hz, 2 H), 2.37 (t, J=7.6, 7.2 Hz,2 H), 2.20 (s, 6 H), 1.77 (q, J=7.6, 7.0 Hz, 2 H), 1.42 (s, 18 H).

EXAMPLE 17 2,6-di-tert-butyl-4-thio((1′-(acetoxy))pentyl)phenol

Reaction Description

2,6-di-tert-butyl-4-thiophenol (0.84 mmol; 200 mg) was dissolved in 7.6mL of DMF and treated with 1.1 mmol (46 mg) of NaH (60% dispersion inmineral oil) to give an orange mixture. After 15 min., 0.76 mmol (0.12mL) of 5-chloropentyl acetate was added. The mixture was stirred for 25h then diluted with 20 mL of EtOAc and washed with H₂O (25 mL). Theorganic layer was washed with brine then concentrated by rotaryevaporation. The crude material was purified by radial chromatography (2mm SiO₂ plate; 85:15 hexanes-EtOAc as eluant) to give2,6-di-tert-butyl-4-thio((1′-(acetoxy))pentyl)phenol (93 mg, 30% yield)as a light yellow, amorphous solid. ¹H NMR (CDCl₃, 400 MHz): δ 7.23 (s,2 H), 5.20 (s, 1 H), 4.05 (app t, J=6.4, 7.2 Hz, 2 H), 2.83 (app t,J=6.8, 7.2 Hz, 2 H), 2.04 (s, 3 H), 1.66-1.58 (br m, 4 H), 1.50-1.42 (brm, 2 H), 1.43 (s, 18 H).

EXAMPLE 182,6-di-tert-butyl-1-methoxy-4-thio(4′-trifluoromethyl)benzyl)benzene

Reaction Description

(2,6-di-tert-butyl-4-thio(4′-(trifluoromethyl)benzyl)phenol (60 mg, 0.15mmol) was taken up in dimethylformamide (0.75 mL), 60% sodium hydride inmineral oil (9 mg, 0.225 mmol) was added followed by methyl iodide(0.014 mL, 0.225 mmol). After 0.5 h the reaction was quenched with 1 NHCl (1 mL) and diluted with ether (10 mL). The ether layer was washedwith water (1×3 mL) and brine (1×3 mL), dried over MgSO₄, filtered, andconcentrated. The resulting oil was purified by radial silica gelchromatography eluting with hexane followed by 1:99 ether/hexane to give20 mg of the product. ¹H NMR (CDCl₃, 400 MHz): δ 7.48 (d, J=8.0 Hz, 2H), 7.20 (d, J=8.0 Hz, 2 H), 7.01 (s, 2 H), 3.93 (s, 2 H), 3.60 (s, 3H), 1.33 (s, 18 H).

EXAMPLE 19 2,6-di-tert-butyl-4-thio(4′-(methyl)phenylethylalcohol))phenol

Reaction Description

The compound of Example 1 (300 mg, 0.86 mmol) was dissolved in THF (17.2mL) and cooled to −78° C. Borane-dimethyl sulfide (2M in THF, 1.72 mL,1.72 mmol) was added and stirred overnight under nitrogen while coolingbath was allowed to warm to room temperature. The reaction was cooled to0° C., and concentrated HCl was added (0.5 mL) and stirred overnight.The solvents in the reaction mixture were removed in vaccuo and theresidue dissolved in ethyl acetate (25 mL), washed with brine (1×5 mL),1N NaOH (1×5 mL), and brine (1×5 mL). The ethyl acetate layer was driedover MgSO₄, filtered, concentrated and chromatographed over silica gelwith 40:60 ether/hexanes to yield 198 mg of product. ¹H NMR (CDCl₃, 400MHz): δ 7.12 (s, 4 H), 7.09 (s, 2 H), 5.21 (s, 1 H), 3.94 (s, 2 H), 3.84(br s, 2 H), 2.84 (t, J=6.8 Hz, 2 H), 1.36 (s, 18 H).

The compounds of formula (II) wherein Z forms an ether group can beprepared by known procedures and techniques, or routine modificationsthereof. A general synthetic scheme for preparing compounds of formula(II) wherein Z forms an ether group is set forth in Scheme B, whereinall substituents, unless otherwise indicated, are previously defined.

Scheme B

A quantity of probucol (commercially available from Sigma Chemicals) ina 0.1 M solution of tetrahydrofuran is treated with 2 equivalents ofsodium hydride and stirred at room temperature for 30 minutes. To thereaction mixture is added 3 equivalent of a primary alkyl bromide oriodide and the reaction stirred at room temperature for 16 hours. Thereaction is quenched with 1 N aqueous HCl and diluted with ethylacetate. The aqueous layer is removed and the ehtyl acetate layer iswashed with water and then with an aqueous saturated sodium chloridesolution. The ethyl acetate solution is dried over magnesium sulfate,gravity or vacuum filtered, and then concentrated. The product ispurified by silica gel chromatography.

An alternative method for the preparation of compounds of formula (II)wherein Z forms an ether group is the treatment of probucol with aprimary alcohol to the method of Mitsunobu (Synthesis, 1981, 1).

A second alternative method for the preparation of compounds of formula(II) wherein Z forms an ether group is the treatment of probucol with aprimary alkyl bromide or iodide in acetonitrile in the presence ofpotassium fluoride absorbed on alumina according to the method of Andoet al. (Bull. Chem. Soc. Jpn., 55, 1982, 2504-2507).

The compounds of formula (II) wherein Z forms an ester group can beprepared by utilizing procedures and techniques well known andappreciated by one of ordinary skill in the art. A general syntheticscheme for preparing compounds of formula (II) wherein Z forms an estergroup is set forth in Scheme C, wherein all substituents, unlessotherwise indicated, are previously defined.

Scheme C

A quantity of probucol in a 0.1 M solution of tetrahydrofuran is treatedwith 2 equivalents of sodium hydride and stirred at room temperature for30 minutes. To the reaction mixture is added 3 equivalents of an acidchloride or acid anhydride and the reaction stirred at room temperaturefor 16 hours. The reaction is quenched with 1 N aqueous HCl and dilutedwith ethyl acetate. The aqueous layer is removed and the ethyl acetatelayer is washed with water and then with an aqueous saturated sodiumchloride solution. The ethyl acetate solution is dried over magnesiumsulfate, gravity or vacuum filtered, and then concentrated. The productis purified by silica gel chromatography.

Starting materials for use in the general synthetic procedures outlinedin the above reaction schemes are readily available or can readily beprepared according to standard techniques and procedures. Probucol isreadily available from Sigma Chemicals.

The following examples present typical syntheses as described in SchemesB and C. These examples are understood to be illustrative only and arenot intended to limit the scope of the present invention in any way.

EXAMPLE 20 Pentanedioic acid,4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-,6-bis(1,1-dimethylethyl)phenylmethyl ester

Reaction Description

Probucol (2.8 g, 5.5 mmol) was taken up in THF (25 mL), 60% sodiumhydride in mineral oil (528 mg, 13.2 mmol) was added followed by theaddition of methyl chloroformyl butyrate (0.751 mL, 6.6 mmol). After 2 hthe reaction was quenched with methanol (3 mL), followed by water (10mL). The reaction mixture was extracted wtih ether (50 mL), concentratedand chromatographed on silica gel eluting with a concentration gradientof 0:100 ether/hexanes to 20:80 ether/hexanes. The reaction yielded 500mg of the product. 7.63 (s, 2 H), 7.45 (s, 2 H), 5.82 (s, 1 H), 3.71 (s,3 H), 2.73 (t, J=7.6 Hz, 2 H), 2.50 (t, J=7.2 Hz, 2 H), 2.07 (pent,J=7.6 Hz, 2 H), 1.47 (s, 6 H), 1.44 (s, 18 H), 1.34 (s, 18 H).

EXAMPLE 21 Phenol,4-[[1-[3,5-bis(1,1-dimethylethy)4-[(4-nitrophenyl)methyoxy]phenyl]thio]-1-methylethyl]thio]2,6-bis(1,1-dimethylethyl)

Reaction Description

A solution of probucol (0.19 mmol; 100 mg) in dry DMF (1 mL) was stirredand treated with sodium hydride (0.28 mmol; 11 mg; 60% dispersion inmineral oil) followed by 4-nitrobenzyl iodide (0.24 mmol; 63 mg). Themixture was stirred for 18 h during which it turned yellow-green. Themixture was quenched with brine then extracted with 3×2 mL of Et₂O. Thecombined organic layers were dried over MgSO₄, filtered, andconcentrated by rotary evaporation to give a brown oil. Purification byradial chromatography (2 mm plate; 1:1 hexanes-CH₂Cl₂ as eluant) gavethe product as a yellow solid (53 mg; 43% yield). ¹H NMR (CDCl₃, 400MHz): δ8.06 (d, J=7.6 Hz, 2 H), 7.35 (s, 2 H), 7.14 (d, J=7.2 Hz, 2 H),6.79 (s, 2 H), 5.41 (s, 1 H), 3.13 (s, 2 H), 1.45-1.43 (overlapping s,21 H), 1.14 (s, 21 H).

EXAMPLE 22 Butanedioic acid, mono[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]2,6-bis(1,1-dimethylethyl)phenyl]ester

Reaction Description

To a 50 mL recovery flask was added probucol (1.0 g, 1.93 mmol) andtetrahydrofuran (16 mL). To the solution was added 60% sodium hydride inmineral oil (0.23 g, 5.75 mmol). To the cloudy white mixture was addedsuccinic anhydride (0.58 g, 5.8 mmol) in THF (12 mL). The reaction darkpurple and was stirred at room temperature for 3 h. The dark purplereaction mixture was made acidic with 1 N HCl (25 mL) and extractedtwice with ethyl acetate (50 mL). The organic extracts were dried overMgSO₄, filtered and concentrated affording an orange solid. The orangesolid was dissolved in ether and chromatographed on silica gel with aconcentration gradient of 70:30 hexane/ether to 0:100 hexane/ether. Theappropriate fractions were combined and concentrated affording a whitesolid. (170 mgm 0.276 mmol, 14%). TLC (silica gel, 60:40 ether/hexane+10drops HOAc, R_(f)=0.35); ¹H NMR (CDCl₃, 400 MHz): δ7.61 (s, 2 H), 7.43(s, 2 H), 5.38 (s, 1 H), 2.97 (t, J=6.8 Hz, 2 H), 2.76 (t, J=6.8 Hz, 2H), 1.45 (s, 8 H), 1.42 (s, 16 H), 1.32 (s, 18 H).

EXAMPLE 23 2-Furancarboxylic acid, 5-nitro,4-[[1-[[3,5-bis)1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis)1,1-dimethylethyl)phenylester

Reaction Description

A solution of 0.39 mmol (200 mg) of probucol in dry THF (3.9 mL) wastreated with sodium hydride (0.58 mmol; 23 mg; 60% dispersion in mineraloil) and stirred for 10 min. at room temperature. The clear mixtureturned purple upon the addition of 4-nitrofuroyl chloride (0.77 mmol;136 mg). The mixture was stirred for 47 h during which it turned brown,and precipitation was observed. The reaction mixture was diluted withEt₂O (40 mL), washed with H₂O (15 mL) then dried over Na₂SO₄ andconcentrated by rotary evaporation to give a crude, yellow-orange solid.Purification by radial chromatography (2 mm SiO₂ plate; 1:1hexanes-CH₂Cl₂ as eluant) gave4,4′-(iospropylidenedithio)[O-(5″-nitro-2″-furoyl)-2′,6′-di-tert-butylphenol]-[2,6-di-tert-butylphenol](83mg; 33% yield). ¹H NMR (CDCl₃, 400 MHz): δ7.70 (s, 2 H), 7.50 (d, J=4.0Hz, 1 H), 7.45 (d, J=3.6 Hz, 1 H), 7.45 (s, 2 H),5.39 (s, 1 H), 1.50 (s,6 H), 1.45 (s, 14 H), 1.35 (s, 22 H).

EXAMPLE 24 Butanoic acid,4-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]2,6-dimethylphenoxyl]

Reaction Description

4,4′-(isopropylidenedithio)[2′,6′-di-methylphenol][2,6-di-tert-butylphenol](0.55 mmol; 0.24 g) was dissolved in dry DMF (5.5 mL). Sodium hydried(1.38 mmol; 33 mg) was added to the mixture followed by methyl4-iodobutyrate (0.83 mmol; 188 mg). The resulting mixture was stirred atroom temperature for 4.5 h during which in turn green. The reaction wasquenched with 0.3 N HCl (ca. 6 mL) causing the mixture to turn yellow.Dilution with Et₂O (25 mL) was followed by washing with H₂O (10 mL) andbrine (10 mL). The solution was dried over MgSO₄ then concentrated byrotary evaporation. Purification by MPLC ((SiO₂; solvent gradient: 100%hexanes then 95:5 hexanes-Et₂O then 90:10 hexanes-Et₂O then 80:20hexanes-Et₂O) gave the desired intermediate as a yellow oil (197 mg; 67%yield). The oil (0.35 mmol; 187 mg) was taken up in 4:1:1 MeOH-THF-H₂)(3.5 mL). LiOH monohydrate (1.05 mmol; 44 mg) was added, and the mixturewas stirred for 1.75 h at room temperature. The reaction mixture wasthen acidified with 0.1 H NCl to pH 4. Extraction with 3×15 mL of EtOActhen drying the combined extracts over MgSO₄ and concentration by rotaryevaporation gave the crude product. Purification by MPLC (SiO₂; solventgradient: 100% hexanes to 60:40 Et₂O-hexanes (acidified with trace ofacetic acid)) gave 4,4′-(isopropylidenedithio) [O-(γ-butyricacid)-2′,6′-di-methylphenol][2,6-di-tert-butylphenol] as a yellow foam(100 mg; 55% yield). ¹H NMR (CDCl₃, 400 MHz): δ 7.44 (s, 2 H), 7.25 (s,2 H), 5.38 (s, 1 H), 3.83 (app t, J=6.0 Hz, 2 H), 2.68 (app t, J=8.0 Hz,2 H), 2.25 (s, 6 H), 2.14 (m, 2 H), 1.47 (s, 6 H), 1.45 (s, 18 H).

EXAMPLE 25 Phenol,4-[[1-[[4-(4-aminobutoxy)-3,5-bis(1,1-dimethylethyl)phenyl]thio]-1-methylethyl]thio]2,6-bis(1,1-dimethylethyl)

Reaction Description

4,4′-(isopropylidenedithio)[2′,6′-di-methylphenol][2,6-di-tert-butylphenol](1.44 mmol; 622 mg) was dissolved in dry DMF (14.4 mL) and treated withsodium hydride (3.6 mmol; 144 mg). Tetrabutylammonium iodide (0.72 mmol;266 mg) was added followed by (N-bromobutyl)phthalimide (2.2 mmol; 608mg). The mixture was stirred at room temperature for 17 h during whichit turned dark green. Teh mixture was quenched with 0.3 N HCl (6 mL)then diluted with Et₂O (100 mL). Washing was done with H₂O (50 mL) andbrine (50 mL). The aqueous layer was treated with NaCl thenback-extracted with Et₂O. The combined organic layers were dried overMgSO₄ then concentrated by rotary evaporation. Purification by MPLC(SiO₂; solvent gradient: 100% hexanes to 75:25 hexanes-Et₂O) gave thedesired intermediate as a yellow-brown oil (750 mg; 82% yield). Theintermediate (0.89 mmol; 563 mg) was dissolved in dry DMF (8.9 mL) andtreated with hydrazine hydrate ((27 mmol; 0.83 mL). The mixture asstirred at room temperature for 42 h. The reaction mixture was treatedwith 1 N HCl (8.9 mL) and stirred for 1.5 h; NaHCO₃ was added to adjustto pH 7 then extracted with EtOAc (2×5 mL) and dried over MgSO₄. solventremoval by rotary evaporation followed by purification by MPLC (SiO₂;solvent gradient: 50:50 MeOH—CH₂Cl₂ to 49.5:49.5:1 MeOH—CH_(2Cl)₂—NH₄OH) gave4,4′-(isopropylidenedithio)[O-(aminobutyl)-2′,6′-di-methylphenol][2,6-di-tert-butylphenol](93 mg; 21% yield). ¹H NMR (CDCl₃400 MHz): δ7.42 (s, 2 H), 7.22 (s, 2H), 5.55 (s, 1 H), 3.76 (app t, J=6.8 Hz, 2 H), 2.78 (app t, J=6.8 Hz, 2H), 2.24 (s, 6 H), 1.83 (m, 2 H), 1.66 (m, 2 H), 1.45 (s, 6 H), 1.42 (s,18 H).

EXAMPLE 26 Phenol,4-[[1-[[4-(4-aminobutyoxy)-3,5-bis)1,1-dimethylethyl)phenyl]thio]-1-methylethyl]thio]2,6-bis(1,1-dimethylethyl)

Reaction Description

Probucol (9.7 mmol; 5 g) was dissolved in dry DMF (14.5 mL) and treatedwith (N-bromobutyl)phthalimide (13.6 mmol; 3.82 g) and KF on alumina(48.4 mmol; 7.03 g). The reaction mixture was stirred at roomtemperature for 18 h then at 80° c. for 4 h. The mixture was filteredthrough a fritted funnel, andthe residue was washed with H₂O (10 mL) andEt₂O (10 mL). The filtrate was diluted with Et₂O (200 mL) then washedwith H₂O (50 mL and brine (50 mL). The combined organic layers weredried over MgSO₄ and concentrated by rotary evaporation. Purification byMPLC (SiO₂; solvent gradient: 100% hexanes to 80:20 hexanes-Et₂O) gavethe desired intermediate as a brown foam (346 mg; 5% yield). Theintermediate (0.44 mmol; 314 mg) was taken up in DMF (4.4 mL) andtreated with hydrazine hydrate (13 mmol; 0.41 mL) to give a green color.The mixture was stirred at room temperature for 16 h then treated with 1N HCl (4.7 mL) and stirred for another 1.5 h. NaHCO₃ was added to adjustthe mixture to pH 7. Extraction with 2×30 mL of EtOAc followed bywashing the organic extracts with brine (20 mL), drying over MgSO₄, andsolvent removal by rotary evaporation gave a green liquid. Purificationby MPLC (SiO₂; solvent gradient: 100% CH₂Cl₂ to 90:10 CH₂Cl₂—MeOH) gave4,4′-(isopropylidenedithio)[O-aminobutyl)-2′,6′-di-tert-butylphenol][2,6-di-tert-butylpheonol]as a yellow solid (182 mg; 71% yield). ¹H NMR (CDCl₃, 400 MHz): δ 7.52(s, 2 H), 7.44 (s, 2 H), 5.28 (s, 1 H), 5.25 (br s, 2 H), 3.72-3.69 (m,2 H), 2.92-2.88 (m, 2 H), 1.94-1.90 (m, 2 H), 1.73-1.69 (m, 2 H), 1.43(s, 22 H), 1.40 (s, 20 H).

EXAMPLE 27 Butanoic acid, 4-hydroxy-,4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenylester

Reaction Description

To a solution of the compound of example 22 (6.17 g, 10 mmol) in THF(200 ml) cooled to −78° C. was slowly added borane-methyl sulfide (10ml, 2 M solution in THF). The reslutant mixture was stirred overnightunder nitrogen while the cooling bth was allowed to warm to roomtemperature. Then it was cooled to 0° C., hydrogen chloride (37%, 4 ml)was added and the mixture was stirred at room temperature overnight. Themixture was evaporated to a residue and distributed between ethylacetate (100 ml) and brine (100 ml). The organic phase was washed with 1N sodium hydroxide solution (100 ml) and then brine (100 ml), dried overmagnesium sulfate and evaporated. Silica gel chromatography(dichloromethane) gave the title compound as a viscous residue.Crystalyzation from hexanes/dichloromethane gave white crystals (5.5 g).MP: 138-139° C. ¹H NMR (400 MHz, CDCl₃): 7.63 (s, 2 H), 7.45 (s, 2 H),5.38 (s, 1 H), 3.76 (t, 2 H), 2.79 (t, 2 H), 2.01 (m, 2 H), 1.47 (s, 6H), 1.44 (s, 18 H), 1.34 (s, 18 H).

EXAMPLE 28 Propanoic acid, 2,2-dimethyl-,[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio-2,6-bis(1,1-dimethylethyl)Phenoxy]methylester

To a suspension of probucol (5.17 g, 10 mmol) in acetonitrile (30 ml)were added chloromethyl pivalate (6.0 g, 40 mmol) and potassium fluoride(8.0 g, 40% on alumina). The resultant mixture was stirred undernitrogen at reflux for 18 hours. After cooled to room temperature it wasfiltered and rinsed with dichloromethane (100 ml). The filtrate waswashed with brine (100 ml), dried over magnesium sulfate and evaporated.Silica gel chromatography (hexanes/dichloromethane 4:1) gave the titlecompound as a yellow oil (0.39 g). ¹H-NMR (400 MHz, CDCl₃): 7.59 (s, 2H), 7.45 (s, 2 H), 5.49 (s, 2 H), 5.38 (s, 1 H), 1.464 (s, 6 H), 1.457(s, 18 H), 1.445 (s, 18 H), 1.28 (s, 9 H).

EXAMPLE 29 Phenol,4-[[1-[[4-(4-aminobutoxy)phenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)

Reaction Description

A solution of:4,4′-(isopropylidenedithio)[phenol][2,6-di-tert-butylphenol] (0.18 mmol;75mg) in 2 mL of dry DMF was stirred and treated with 0.23 mmol (9 mg)of sodium hydride (60% dispersion in mineral oil) to give a yellowmixture. N-(4-bromobutyl)phthalimide (0.22 mmol; 63 mg) was addedfollowed by 0.22 mmol (33 mg) of NaI. The mixture was heated to 120° C.,turning a dark green color. After 24 h, TLC (SiO₂; CH₂Cl₂ as eluant;visualization by UV, PMA/char) showed only traces of starting materialpresent. The reaction mixture was cooled to room temperature thenquenched with 3 mL each of Et₂O and sat. NaCl. The aqueous layer wasback-extracted with 3 mL of Et₂O; the combined organic layers were driedover MgSO₄, filtered, and concentrated by rotary evaporation to give adark brown oil. Purification by column chromatography (SiO₂; 20×170 mmcolumn; CH₂Cl₂ as eluant) gave the desired intermediate in 69% yield (69mg). The intermediate (0.11 mmol; 69 mg) was taken up in 1 mL of DMF andstirred. Hydrazine hydrate (0.16 mmol; 8 μL) was added, causing colorchange from yellow to deep blue-green. The reaction mixture was stirredat room temperature for 1 week by which time it had turned a clearyellow. TLC showed the presence of starting material. Additionalhydrazine hydrate (10.3 mmol; 0.5 mL) was added; the mixture was stirredfor another 24 h, after which starting material was completely consumed.The mixture was quenched with 12 N HCl to adjust the pH to 3. Afterstirring for 5 min., sat. NaHCO₃ was added to neutralize the acid (finalpH=7). EtOAC was added, and the aqueous layer was back-extracted with2×2 mL of EtOAc. The combined organic layers were dried over MgSO₄,filtered and concentrated by rotary evaporation. The crude product waspurified by column chromatography (SiO₂; 15×110 mm column; EtOH aseluant) to give4,4′-(isopropylidenedithio)[O-(aminobutyl)phenol][2,6-di-tert-butylphenol](25 mg; 48% yield) as a yellow solid. ¹H NMR (CDCl₃, 400 MHz): δ7.50 (d,J=8.4 Hz, 2 H), 7.42 (s, 2 H), 6.83 (d, J=8.4 Hz, 2 H), 5.36 (br s, 1H), 3.97 (br m, 2 H), 3.10 (br m, 2 H), 2.01-1.86 (overlapping m, 4 H),1.43 (s, 24 H).

EXAMPLE 30 Butanoic acid,4-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]phenoxy]

Reaction Description

A solution of:4,4′-(isopropylidenedithio)[phenol][2,6-di-tert-butylphenol] (0.6 mmol;242 mg) in 6 mL of dry DMF was stirred and treated with 1.3 mmol (53 mg)of sodium hydride (60% dispersion in mineral oil) to give a brownsolution. The reaction mixture was treated with 0.9 mmol (131 μL) ofmethyl 4-iodobutyrate. The progress of the reaction was monitored by TLCusing CH₂Cl₂ as eluant (visualization by UV, PMA/char). After 24 h, TLCof the dark green mixture showed predominantly product. The mixture wasquenched with sat. NaCl and Et₂O. The aqueous layer was back-extractedwith 2×6 mL of Et₂O; the combined organic layers were dried over MgSO₄,filtered, and concentrated by rotary evaporation to give a crude oil.Column chromatography (SiO₂; 20×185 mm column) using CH₂Cl₂ gave 232mg(77% yield) of the desired intermediate which was taken up and stirredin 3 mL of 4:1:1 MeOH—THF—H₂O. The pale yellow solution was treated with0.92 mmol (39 mg) of LiOH monohydrate to give a greenish-yellowsolution. The mixture was stirred at room temperature until all startingmaterial was consumed (ca. 18 H0 then treated with 12 N HCl to adjustthe pH to 2 (yellow mixture). Et₂O (5 mL) was added; the aqueous layerwas back-extracted with 2×5 mL of Et₂O. The combined organic layers weredried over MgSO₄, filtered then concentrated by rotary evaporation togive a crude solid. Purification by column chromatography (SiO₂; 15×180mm column; 3:1 hexanes-EtOH as eluant) gave4,4′-(isopropylidenedithio)[O-(γ-butyricacid)phenol][2,6-di-tert-butylphenol] as an oil (62 mg; 40% yield). ¹HNMR (CDCl₃, 400 MHz): δ7.47 (d, J=8.0 Hz, 2 H), 7.40 (s, 2 H), 6.80 (d,J=7.6 Hz, 2 H), 5.35 (s, 1 H), 3.93 (br m, 2 H), 2.51 (br m, 2 H), 2.07(br m, 2 H), 1.42 (s, 18 H), 1.25 (s, 6 H).

EXAMPLE 31 Acetic acid,[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]2,6-bis(1,1-dimethylethyl)phenoxy]

Reaction Description

To dimethylformamide (1.5 mL) was added probucol(0.5 g, 0.967 mmol) andethyl-2-iodo acetate (0.31 g, 1.45 mmol) and 40% potassium fluoride onalumina (0.7 g) and the reaction was stirred for 24 hours. The reactionmixture was diluted with ether (25 mL), filtered and washed with water(2×5 mL). The ether layer was dried over MgSO₄, filtered andconcentrated. The resulting oil was purified by radial silica gelchromatography by elution with 5:95 ether/hexanes to yield 160 mg of theethyl ester of the product. The ethyl ester dissolved inTHF:H₂0:MeOH(4:1:1)(4 mL) and LiOH—H₂0 (50 mg) was added and thereaction stirred for 1 h. The reaction was neutralized with 1 N HCl andextracted with ether (2×10 mL), dried over MgSO₄, filtered, andconcentrated. Silica gel chromatography and elution with 50:50ether/hexanes gave 90 mg of the product. ¹H NMR (CDCl₃, 400 MHz): δ7.55(s, 2 H), 7.40 (s, 2 H), 5.35 (s, 1 H), 4.40 (s, 2 H), 1.43 (s, 6 H),1.41 (s, 9 H), 1.39 (s, 9 H).

EXAMPLE 32 Glycine, 4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenylester

Reaction Description

To a solution of probucol (3.0 g, 5.8 mmol) in THF (58 mL) was added 60%sodium hydride (1.16 g, 29.0 mmol) and the reaction stirred for 0.5 h atroom temperature. The acid chloride of phthaloyl glycine was added andthe reaction stirred an additional 0.5 h. The reaction was then dilutedwith ethyl acetate (150 mL), quenched with water (5 mL), then washedwith water (2×50 mL) and brine (1×50 mL). The organic layer was driedover MgSO4, filtered and concentrated. The resulting oil waschromatographed on silica gel eluting with 10% ethyl acetate/hexanefollowed by 20% ethyl acetate/hexane to yield 610 mg of the phthaloylglycine ester. The phthaloyl glycine ester was taken up in DMF(8.6 mL)and hydrazine hydrate was added (0.136 mL, 2.34 mmol) and the reactionstirred overnight. 1 H NCl was added (5 mL) and the reaction stirred anadditional 1 h. The reaction was diluted with ethyl acetate (25 mL) andwashed with NaHCO3 (aq) (1×10 mL). The ethyl acetate layer was driedover MgSO₄, filtered, concentrated, and chromatographed on silica gel,eluting with 1% methanol/methylene chloride followed by 1.5%methanol/methylene chloride to yield 334 mg of product. 7.64 (s, 2 H),7.45 (s, 2 H), 5.39 (br s, 1 H), 3.76 (s, 2 H), 1.48 (s, 6 H), 1.44 (s,18 H), 1.33 (s, 18 H).

EXAMPLE 33 Pentanedioic acid,Mmono[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenyl]]ester

Reaction Description

To a 50 mL recovery flask was added probucol (1.0 g, 1.93 mmol) andtetrahydrofuran (20 mL). To the solution was added 60% sodium hydride inmineral oil (0.16 g, 4 mmol). To the cloudy white mixture was addedglutaric anhydride (0.170 g, 3 mmol) in THF (12 mL). The reaction wasstirred at room temperature for 3 h. The reaction mixture was madeacidic with 1 N HCl (25 mL) and extracted twice with ethyl acetate (50mL). The organic extracts were dried over MgSO₄, filtered andconcentrated affording a yellow oil. The yellow oil was dissolved inether and chromatographed on silica gel with a concentration gradient of70:30 hexane/ether to 0:100 hexane/ether. The appropriate fractions werecombined and concentrated affording a white solid. 7.62 (s, 2 H), 7.45(s, 2 H), 5.37 (s, 1 H), 2.75 (t, J=7.2 Hz, 2 H), 2.55 (t, J=7.2 Hz, 2H), 2.09 (m, 2 H), 1.47 (s, 6 H), 1.44 (s, 18 H), 1.43 (H).

EXAMPLE 34 Butanoic acid,4-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]

Reaction Description

Probucol (5 g, 9.7 mmol) was stirred together with methyl 4-iodobutyrate(3.1 g, 13.6 mmol) in DMF (15 mL). To the reaction mixture was added 40%potassium flouride on alumina (7 g, 48 mmol) and stirring continued atroom temperature overnight. The green reaction mixture was filtered intoa separatory funnel, diluted with ethyl acetate (50 mL) and washed withwater (2×20 mL) and saturated aqueous sodium chloride (1×20 mL). Theethyl acetate layer was dried over MgSO₄, fileterd, concentrated andchromatographed on silia gel by elution with a concentration gradient of10:90 methylene chloride/hexane to 60:40 methylene chloride hexane. Theappropriate fractions were collected and concentrated to afford 442 mgof a white solid. The methyl ester was taken up in THF:MeOH:H₂0(4:1:1)(5 mL) and lithium hydroxide (63 mg, 1.5 mmol) wa added. After2.5 h the reaction was complete and quenched with 1 N HCl (3 mL) andextracted with ethyl acetate (15 mL). The ethyl acetate solution waswashed with saturated aqueous sodium chloride (3 mL), dried over MgSO₄,filtered and concentrated. Chromatography over silica gel, eluting witha solvent gradient of 10:90 ether/hexanes to 50:50 ether/hexanesafforded 308 mg of product. 7.53 (s, 2 H), 7.45 (s, 2 H), 5.37 (s, 1 H),3.77 (t, J=6.8 Hz, 2 H), 2.55 (t, J=7.6 Hz, 2 H),2.16 (m, 2 H), 1.44 (s,24 H), 1.41 (s, 18 H).

EXAMPLE 35 Oxiranemethanol,α-[[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]methyl]Oxiranemethanol,3-[[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]methyl]Oxiranemethanol,α-[[[3-[[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]methyl]oxiranyl]methoxy]methyl]

To a solution of probucol (5.16 g, 10 mmol) in acetonitrile (50 ml) wereadded 1,3-butadiene diepoxide (1.6 ml, 20 mmol) and potassium fluoride(2.9 g, 20 mmol, 40% on alumina). The resultant mixture was stirredunder nitrogen at reflux for 18 hours. After cooled to room temperatureit was poured into dichloromethane (150 ml), washed with water (2×100ml), dried over magnesium and evaporated. Silica gel chromatography(hexanes/dichloromethane 2:1, 1:1, 1:2 and then dichloromethane) gaveOxiranemethanol,α-[[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6bis(1,1-dimethylethyl)phenoxy]methyl]- (0.47 g), Oxiranemethanol,3-[[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]methyl]- (0.15 g) and Oxiranemethanol,α-[[[3-[[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenly]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]methyl]oxiranyl]methoxy]methyl]- (0.05 g).

Oxiranemethanol,α-[[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]methyl]

¹H-NMR ( 400 MHz, CDCl₃): 7.56 (s, 2 H), 7.45 (s, 2 H), 5.38 (s, 1 H),4.10-4.17 (m, 1 H), 3.83-3.97 (m, 2 H), 3.27-3.32 (m, 1 H), 2.83-2.94(m, 2 H), 2.18 (br. s, 1 H), 1.46 (s, 6 H), 1.45 (s, 18 H), 1.44 (s, 18H).

Oxiranemethanol,3-[[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1--methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]methoxyl]

¹H-NMR (400 MHz, CDCl₃): 7.56 (s, 2 H), 7.45 (s, 2 H), 5.39 (s, 1 H),4.38 (m, 2 H), 4.00 (m, 2 H), 3.89 (m, 2 H), 1.34-1.41 (m, 42 H).

Oxiranemethanol,α-[[[3-[[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]methyl]oxiranyl]methoxy]methyl]

¹H-NMR (400 MHz, CDCl₃): 7.54 (s, 2 H), 7.45 (s, 2 H), 5.39 (s, 1 H),4.24 (br. m, 1 H), 3.93 (m, 1 H), 3.81 (m, 1 H), 3.77 (br. m, 1 H), 3.16(m, 1 H), 3.06 (m, 1 H), 2.91 (m, 1 H), 2.85 (m, 2 H), 2.84 (m, 1H),2.75 (m, 2 H), 1.41-1.44 (m, 42 H).

EXAMPLE 36 Phenol,4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-(oxiranylmethoxy)phenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)

To a solution of probucol (2,58 g, 5 mmol) in THF (50 ml) cooled to 0°C. were added glycidol (0.66 ml, 10 mmol), triphenyl phosphine (2.62g,10 mmol), and diethylazodicarboxylate (1.57 ml, 10 mmol). Theresultant mixture was stirred under nitrogen at reflux for 48 hours andthen evaporated. Silica gel chromatography (hexanes/dichloromethane 4:1,2:1) gave the title compound as a viscous residue (1.01 g). ¹H-NMR (400MHz, CDCl₃): 7.56 (s, 2 H), 7.44 (s, 2 H), 5.39 (s, 1 H), 4.40 (m, 1 H),3.75 (m, 1 H), 3.39 (m, 1 H), 2.91 (m, 1 H), 2.77 (m, 1 H), 1.40-1.49(m, 42 H).

EXAMPLE 37 Glycine,N-[3-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]2-hydroxypropyl]

To suspension of Phenol,4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-(oxiranylmethoxy)phenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)-(0.17g, 0.28 mmol) in ethanol (10 ml) were added glycine (43 mg, 0.57 mmol)and triethylamine (1 ml). The resultant mixture was stirred undernitrogen at reflux overnight. The mixture became a solution uponheating. It was then evaporated. Silica gel chromatography(dichloromethane/methanol 10:1 1:1) give the title compound (99 mg).¹H-NMR (400 MHz, CDCl₃): 7.52 (s, 2 H), 7.43 (s, 2 H), 5.37 (s, 1 H),4.58 (br. s, 1 H), 3.79 (br. m, 2 H), 3.67 (m, 1 H), 3.30 (m, 1 H), 3.21(m, 1 H), 3.13 (m, 1 H), 1.43 (s, 18 H), 1.41 (s, 6 H), 1.38 (s, 18 H).

EXAMPLE 38 1,2,3-butanetriol,4-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]=1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]-2-Hydroxypropyl]

To a solution of Oxiranemethanol,α-[[4-[[1-[[3,5-Bis(1,1-Dimethylethyl)-4-Hydroxyphenyl]Thio]-1-Methylethyl]Thio]-2,6-Bis(1,1-dimethylethyl)phenoxy]methyl]-(0.15 g) in actonitrile (5 ml) were added water (1 ml) and concetratedsulfuric acid (10 drops). The resultant mixture was stirred at roomtemperature for 48 hours and then poured into brine (50 ml), extractedwith dichloromethane (3×50 ml), dried over magnesium sulfate andevaporated. Silica gel chromatography (dichloromethane/ethyl acetate3:1) gave the title compound as a colorless viscous residue (26 mg).¹H-NMR (400 MHz, CDCl₃): 7.54 (s, 2 H), 7.43 (s, 2 H), 5.36 (s, 1 H),4.27 (m, 2 H), 3.98 (m, 2 H), 3.75 (m, 2 H), 1.36-1.44 (m, 42 H).

EXAMPLE 39 Phenol, 4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-(3-ethoxy-2-hydroxypropoxy)phenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)1,2-propanediol,3-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]

To a suspension of Oxiranemethanol,α-[[[3-[[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]methyl]oxiranyl]methoxy]methyl]- (0.32 g) inethanol (10 ml) was added 1 N sodium hydroxide solution (1.5 ml). Theresultant mixture was stirred at reflux for three days and thenevaporated. The residue was distributed between ethyl acetate (50 ml)and brine (50 ml). The organic phase was washed with brine (50 ml),dried over magnesium sulfate and evaporated. Silica gel chromatography(hexanes/dichloromethane 1:1, dichloromethane and thendichloromethane/ethyl acetate 4:1) afforded 1,2-Propanediol,3-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]- (58 mg) and a mixture that contained thePhenol,4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-(3-ethoxy-2-hydroxypropoxy)phenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)-,which was re-columned (hexanes/ethyl acetate 5:1) and Phenol,4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-(3-ethoxy-2-hydroxypropoxy)phenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)- was obtained in pure form (52 mg).

Phenol,4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-(3-ethoxy-2-hydroxypropoxy)phenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)

¹H-NMR (400 MHz, CDCl₃): 7.55 (s, 2 H), 7.45 (s, 2 H), 5.38 (s, 1 H),4.35 (m, 1 H), 4.11 (m, 1 H), 3.83 (m, 2 H), 3.62 (m, 1 H), 3.57 (m, 2H), 1.43-1.46 (m, 42 H), 1.22 (t, 3 H).

1,2-propanediol,3-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]

¹H-NMR (400 MHz, CDCl₃): 7.56 (s, 2 H), 7.45 (s, 2 H), 5.38 (s, 1 H),4.32 (m, 1 H), 3.94 (dd, 1 H), 3.85 (m, 1 H), 3.77 (m, 1 H), 3.66 (m, 1H), 1.40-1.44 (m, 42 H).

EXAMPLE 40 Phenol,4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-ethoxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)2-Propenoic acid,3-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxyl]-,ethyl ester, (e) 2-Propenic acid,3-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-ethoxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]-,ethyl ester, (E)

To a solution of probucol (5.16 g, 10 mmol) in THF (50 ml) were addedethyl propiolate (1.2 ml, 12 mmol) and triethylamine (7 ml, 50 mmol).The resultant mixture was stirred under nitrogen at reflux over weekend.After cooled to room temperature it was poured into brine (100 ml),extracted wtih dichloromethame (3×100 ml), dried over magnesium sulfateand evaporated. Silica gel chromatography (hexanes/dichloromethane 9:1to straight dichloromethane) gave Phenol,4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-ethoxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)-;(0.51 g), 2-Propenoic acid,3-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-ethoxyphenyl]thio-]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]-,ethyl ester, (E)-; (0.37 g) and 2 -Propenoic acid,3-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]-,ethyl ester (E)- (0.54 g).

Phenol,4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-ethoxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)

¹H-NMR (400 MHz, CDCl₃): 7.52 (s, 2 H), 7.45 (s, 2 H), 5.37 (s, 1 H),3.76 (quad., 2 H), 1.39-1.45 (m, 45 H).

2-Propenoic acid,3-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]-,ethyl ester, (E)

¹H-NMR (400 MHz, CDCl₃): 7.62 (s, 2 H), 7.44 (s, 2 H), 6.40 (d, 1 H),5.38 (s, 1 H), 5.02 (d, 1 H), 4.23 (quad., 2 H), 1.47 (s, 6 H), 1.44 (s,18 H), 1.42 (s, 18 H), 1.30 (t, 3 H).

2-Propenoic acid,3-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-ethoxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]-,ethyl ester, (E)

¹H-NMR (400 MHz, CDCl3): 7.62 (s, 2 H), 7.51 (s, 2 H), 6.40 (d, 1 H),5.03 (d, 1 H), 4.23 (quad., 2 H), 3.76 (quad., 2 H), 1.25-1.48 (m, 48H).

EXAMPLE 41 Butanedioic acid,mono[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-methoxyphenyl]thio]1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenyl]ester

Reaction Description

The compound of Example 22 (1.13 g, 1.83 mmol) was taken up in DMF (3.6mL) and 60% sodium hydride (183 mg, 4.6 mmol) was added followed 0.25 hlater by methyl iodide (0.342 mL, 5.5 mmol). The reaction was allowed tostir overnight. The reaction was quenched with water (2 mL), dilutedwith ether (50 mL). The ether layer was washed with water (2×10 mL) andsaturated aqueous sodium chloride (1×10 mL), dried over MgSO₄, filtere,and concentrated. Column chromatography over silica gel and elution witha concentration gradient of 0:100 ether/hexane to 40:60 ether/hexanegave 556 mg of dimethylated product. The product was taken up inTHF:MeOH:H₂0 (4:1:1)(5 mL) and lithium hydroxide (63 mg, 1.5 mmol) wasadded. After 2.5 h the reaction was complete and quenched with 1 N HCl(3 mL) and extracted with ethyl acetate (15 mL). The ethyl acetatesolution was washed with saturated aqueous sodium chloride (3 mL), driedover MgSO₄, filtered and concentrated. Chromatography over silica gel,eluting with a solvent gradient of 10:90 ether/hexanes to 50:50ether/hexanes afforded 400 mg of product. ¹H NMR (CDCl₃, 400 MHz): δ7.62(s, 2 H), 7.45 (s, 2 H), 5.37 (s, 1 H), 3.71 (s, 3 H), 2.75 (t, J=7.2Hz, 2 H), 2.55 (t, J=7.2 Hz, 2 H), 2.09 (m, 2 H), 1.46 (s, 6 H), 1.44(s, 18 H), 1.42 (s, 18 H).

EXAMPLE 42 Phenol,4-[[1-[[4-[2-[4-(dimethylamino)phenyl]ethoxy]-3,5-bis(1,1-dimethylethyl)phenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)

Reaction Description

Probucol (1.16 mmol; 600 mg) was dissolved in THF (11.6 mL) and treatedwith triphenylphosphine (2.3 mmol; 608 mg), diethyl azodicarboxylate(2.3 mmol; 0.37 mL), and 4-(dimethylamino)phenethyl alcohol (2.3 mmol;383 mg). The brown mixture was stirred under reflux for 41.5 h. Solventwas removed by rotary evaportion to give a brown oil. Purification bychromatography gave4,4′-(isopropylidenedithio)[O-(4″-(dimethylamino)phenethyl)-2′,6′-di-tert-butylphenol][2,6-di-tert-butylphenol] as an oil (256 mg; 33%yield) ¹H NMR (CDCl₃, 400 MHz): δ7.52 (s, 2 H), 7.45 (s, 2 H), 7.12 (d,J=8.4 Hz, 2 H), 6.74 (br d, J =8.0 Hz, 2 H), 5.38 (s, 1 H), 3.84 (app t,J=8.0, 8.8 Hz, 2 H), 3.09 (app t, J =7.6, 8.8 Hz, 2 H), 2.93 (s, 6 H),1.45-1.44 (overlapping s, 42 H).

EXAMPLE 43 Benzenamine,4,4′-[(1-methylethylidene)bis[thio[2,6-bis(1,1-dimethylethyl)-4,1-phenylene]oxy-2,1-ethanediyl]]bis[N,N-dimethyl

Reaction Description

Probucol (1.16 mmol; 600 mg) was dissolved in THF (11.6 mL) and treatedwith triphenylphosphine (2.3 mmol; 608 mg), diethyl azodicarboxylate(2.3 mmol; 0.37 mL), and 4-(dimethylamino)phenethyl alcohol (2.3 mmol;383 mg). The brown mixture was stirred under reflux for 41.5 h. Solventwas removed by rotary evaporation to give a brown oil. Purification bychromatography gave4,4′-(isopropylidenedithio)bis[(4″-(dimethylamino)phenethyl)-2,6-di-tert-butylphenol]]asa light pink solid (155 mg; 16% yield) ¹H NMR (CDCl₃, 400 MHz): δ7.50(s, 4 H), 7.12 (d, J=8.8 Hz, 4 H), 6.74 (br d, J=8.0 Hz, 4 H), 3.84 (appt, J=7.6, 8.8 Hz, 4 H), 3.09 (app t, J=8.0, 8.8 Hz, 4 H), 2.93 (s, 12H), 1.43-1.42 (overlapping s, 42 H).

EXAMPLE 44 L-Arginine,mono[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenylbutanedioate]

Reaction Description

To a solution of the compound of Example 22 (1.67 g, 2.7 mmol) inmethanol (30 ml) was added L-arginine (0.47 g, 2.7 mmol). The resultantmixture was stirred at room temperature for 2 hours and then filtered.The filtrate was evaporated and the residue was dissolved in minimumamount of ether. Then hexanes was added to precipitate out the titlecompound. It was filtered and dried on vacuum to afford a off-whitesolid (1.75 g). MP: 185-190° C. ¹H-NMR (400 MHz, CDCl3): 7.60 (s, 2 H),7.42 (s, 2 H), 5.37 (s, 1 H), 3.64 (br. s, 1 H), 3.11 (br. s, 2 H), 2.96(br. s, 2 H), 2.58 (br. s, 2 H), 1.41-1.44 (m, 26 H), 1.23-1.31 (m, 20H).

EXAMPLE 45 2-Propenoic acid,3-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]-,(E)

To a solution of 2-Propenoic acid,3-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]-,ethyl ester, (E)- (0.16 g, 0.26 mmol) in THF (5 ml) were added water (2ml) and lithium hydroxide monohydrate (42 mg, 1 mmol). The resultantmixture was stirred at reflux overnight. After cooled to roomtemperature it was poured into dichloromethane (50 ml), washed withbrine, dried over magnesium sulfate and evaporated. Silica gelchromatography (hexanes/ethyl acetate 4:1) gave the title compound as aviscous residue (22 mg). ¹H-NMR (400 MHz, CDCl3): 7.63 (s, 2 H), 7.44(s, 2 H), 6.52 (d, 1 H), 5.39 (s, 1 H), 5.08 (d, 1 H), 1.47 (s, 6 H),1.44 (s, 18 H), 1.42 (s, 18 H).

EXAMPLE 46 α-D-Galactopyranose,6-O-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenyl]-1,2:3,4-bis-O-(1-methylethylidene)

To a solution of probucol (2.58 g, 5 mmol) and1,2,3,4-di-O-isopropylidene-D-galactopyranose (1.8 ml, 10 mmol) in THF(100 ML) were added triphenylphosphine (2.62 g, 10 mmol) and diethylazodicarboxylate (1.57 ml, 10 mmol). The resultant mixture was stirredunder nitrogen at reflux 72 hours. It was evaporated. Silica gelchromatography (cyclohexane/ethyl acetate 30:1) gave the title compound(0.16 g). ¹H-NMR (400 MHz, CDCl3): 7.53 (s, 2 H), 7.45 (s, 2 H), 5.60(s, 1 H), 4.65 (m, 2 H), 4.35 (m, 4 H), 1.59 (s, 6 H), 1.44 (s, 18 H),1.43 (s, 18 H),1.37 (s, 6 H), 1.33 (s, 6 H).

EXAMPLE 47 Phenol,4-[[1-[[4-[3-(dimethylamino)propoxy[-3,5-bis(1,1-dimethylethyl)phenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)

Reaction Descrition

Probucol (0.5 g, 0.97 mmol) was dissolved in THF, cooled to 0° C., and3-hydroxypropyldiethyl amine (0.287 mL, 1.94 mmol) was added followed bythe addition of triphenylphosphine (0.508 g, 1.94 mmol) and diethylazodicarboxylate (0.31 mL, 1.94 mmol). The reaction was heated to refluxand reflux continued for 30 h. The reaction mixture was concentrated andpurified by silica gel chromatography eluting with 20:80 methanol/etherto give the product. ¹H NMR (CDCl₃, 400 MHz): δ7.52 (s, 2 H), 7.27 (s, 2H), 3.74 (t, J=1.6 Hz, 2 H), 2.56 (q, J=7.2 Hz, 2 H), 2.03 (pent, J=7.6Hz, 2 H), 1.44 (q, J=3.2 Hz, 4 H), 1.42 (s, 24 H), 1.25 (t, J=3.3 Hz, 6H).

EXAMPLE 48 Glycine,N-[[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1,methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]acetyl]

Reaction Description

To Acetic acid,[4-[[1-3,5-bis(1,1-dimethylethyl)-4-hydrocyphenyl]thio]-1-methylethyl]thio]2,6-bis(1,1-dimethylethylphenoxy)-(50 mg, 0.087 mmol) in methylene chloride (0.87 mL) was added glycineethyl ester hydrochloride (15.8 mg, 0.11 mmol),1-(3-dimethylaminopropyl-3-ethyl carbodiimide hydrochloride(22 mg, 0.11mmol) and dimethylaminopyridine (28 mg, 0.23 mmol). The reaction mixturewas stirred overnight and the methylene chloride evaporated. Thereaction was diluted with ether (10 mL) and washed with water (2×3 mL),dried over MgSO₄, filtered, and concentrated. The crude mixture waspurified by silica gel chromatography and elution with 50:50ether/hexane to give 50 mg of the ethyl ester of the product. The ethylester dissolved in THF:H₂O:MeOH (2:1:1)(1 mL) and LiOH—H2O (15 mg) wasadded and the reaction stirred for 1 h. The reaction was neutralizedwith 1N HCl and extracted with ether (2×10 mL), dried over MgSO₄,filtered, and concentrated to give 25 mg of product. ¹H NMR (CDCl₃, 400MHz): δ 7.56 (s, 2 H), 7.42 (s, 2 H), 5.39 (br s, 1 H), 4.31 (s, 2 H),4.22 (d, J=5.2 Hz, 2 H), 1.44 (s, 6 H), 1.42 (s, 9 H), 1.39 (s, 9 H).

EXAMPLE 49 Glutamic acid,N-[[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]acetyl]

Reaction Description

To Acetic acid,[4-[[1-3,5-bis(1,1-dimethylethyl)-4-hydrocyphenyl]thio]-1-methylethyl]thio]2,6-bis(1,1-dimethylethylphenoxy)-(100 mg, 0.174 mmol) in methylene chloride (1.8 mL) was added glutamicacid diethylester hydrochloride (54 mg, 0.22 mmol),1-(3-dimethylaminopropyl-3-ethyl carbodiimide hydrochloride(44 mg, 0.22mmol) and dimethylaminopyridine(55 mg, 0.45 mmol). The reaction mixturewas stirred overnight and the methylene chloride evaporated. Thereaction was diluted with ether(10 mL) and washed with water(2×3 mL),dried over MgSO₄, filtered, and concentrated. The crude mixture waspurified by silica gel chromatography and elution with 50:50ether/hexane to give 130 mg of the diethyl ester of the desired product.The diethyl ester was dissolved in THF:H₂O:MeOH(2:1:1)(3 mL) andLiOH—H₂O (100 mg) was added and the reaction stirred for 1 h. Thereaction was neutralized with 1N HCl and extracted with ether (2×10 mL),dried over MgSO₄, filtered, and concentrated to give 45 mg of product.¹H NMR (CDCl₃, 400 MHz): δ 7.57 (s, 2 H), 7.42 (s, 2 H), 5.37 (s, 1 H),4.83 (m, 1 H), 4.28 (s, 2 H), 2.56 (m, 2 H), 1.44 (s, 6 H), 1.43 (s, 9H), 1.41 (s, 9 H).

EXAMPLE 50 L-Glutamic acid,N-[3-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]-2-hydroxypropyl]-di-,diethyl ester

Reaction Description

To a suspension of Phenol,4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-(oxiranylmethoxy)phenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)-(0.12 g, 0.20 mmol) and L-glutamic acid diethyl ester hydrochloride(0.24 g, 1 mmol) in ethanol (15 ml) was added triethylamine (2 ml). Theresultant mixture was stirred under nitrogen at reflux for 18 hours. Itwas evaporated. Silica gel chromatography (dichloromethane/methanol 5:1)gave a yellow oil which was re-columned (dichloromethane/methanol 10:1)to give the title compound as a white viscous residue (16 mg). ¹H-NMR(400 MHz, CDCl₃): 7.53 (s, 2 H), 7.42 (s, 2 H), 5.36 (s, 1 H), 4.90 (m,1 H), 3.85 (m, 2 H), 3.55-3.75 (m, 7 H), 2.01 (m, 2 H), 1.39-1.42 (m, 48H), 1.23 (m, 2 H).

EXAMPLE 51 2-Propenoic acid,4-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]butylester

To a solution of probucol (2.58 g, 5 mmol) in THF (50 ML) were added4-hydroxybutyl acrylate (1.0 ml, 10 mmol), triphenylphosphine (2.62 g,10 mmol) and diethyl azodicarboxylate (1.57 ml, 10 mmol). The resultantmixture was stirred under nitrogen at reflux over weekend. It wasevaporated. Silica gel chromatography (hexanes/dichloromethane 4:1) gavethe title compound as a brown oil (0.92 g). ¹H-NMR (400 MHz, CDCl₃):7.54 (s, 2 H), 7.46 (s, 2 H), 6.42 (dd, 1 H), 6.14 (dd, 1 H), 5.84 (dd,1 H), 5.38 (s, 1 H), 4.23 (t, 2 H), 3.75 (t, 2 H), 1.97 (m, 2 H), 1.82(m, 2 H), 1.46 (s, 6 H), 1.45 (s, 18 H), 1.42 (s, 18 H).

EXAMPLE 52 Phenol,4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-(4-hydroxybutoxy)phenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)

To a suspension of 2-Propenoic acid,4-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]butylester (0.82 g) in methanol (20 ml) was added potassium carbonate (0.5g). The resultant mixture was stirred under nitrogen at room temperatureovernight. It was poured into water (50 ml), extracted withdichloromethane (2×50 ml), dried over magnesium fulfate and evaporated.Silica gel chromatography (hexanes/ethyl acetate 4:1) gave the titlecompound as a colorless oil (0.52 g). ¹H-NMR (400 MHz, CDCl₃): 7.54 (s,2 H), 7.46 (s, 2 H), 3.71-3.77 (m, 4 H), 1.96 (m, 2H), 1.72 (m, 2 H),1.46 (s, 6 H), 1.45 (s, 18 H), 1.43 (s, 18 H).

EXAMPLE 53 β-D-Glucopyranose,6-O-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenyl]

To a solution of probucol (1.8 g, 3.5 mmol) in THF (20 ML) were added1,2,3,4-tetra-O-actyl-β-D-glucopyranose (1.0 g, 2.9 mmol),triphenylphosphine (0.92 g, 3.5 mmol) and diethyl azodicarboxylate (0.55ml, 3.5 mmol). The resultant mixture was stirred under nitrogen atreflux for two hours. It was evaporated. Silica gel chromatography(hexanes/ethyl acetate 4:1) gave the title compound as an off-whitesolid (0.92 g). ¹H-NMR (400 MHz, CDCl3): 7.53 (s, 2 H), 7.45 (s, 2 H),5.80 (d, 1 H), 5.38 (s, 1 H), 5.33 (dd, 1 H), 5.16 (dd, 1 H), 4.90 (dd,1 H), 4.19 (m, 1 H), 3.88 (m, 1 H), 3.74 (m, 1 H), 2.14 (s, 3 H), 2.06(s, 3 H), 2.03 (s, 3 H), 2.02 (s, 3 H), 1.45 (s, 18+6 H), 1.38 (s, 18H).

EXAMPLE 54 1-H-Tetrazole-1-butanoic acid,4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenylester

To a solution of Butanoic acid, 4-hydorxy-,4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenylester (60 mg, 0.1 mmol) in THF (10 ML) were added 1H-tetrazole 14 mg,0.2 mmol), triphenylphosphine (52 mg, 0.2 mmol) and diethylazodicarboxylate (0.03 ml, 0.2 mmol). The resultant mixture was stirredunder nitrogen at reflux for 2 hours. It was evaporated. Silica gelchromatography (hexanes/ethyl acetate 4:1) gave the title compound as anoil (57 mg). ¹H-NMR (400 MHz, CDCl₃): 8.56 (s, 1 H), 7.64 (s, 2 H), 7.45(s, 2 H), 5.39 (s, 1 H), 4.84 (t, 2 H), 2.74 (t, 2 H), 2.47 (m, 2 H),1.47 (s, 6 H), 1.45 (s, 18 H), 1.33 (s, 18 H).

EXAMPLE 55 Phenol,4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-[[3-hydroxy-1-propenyl)oxy]phenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)

To a solution of 2-Propenoic acid,3-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]-,ethyl ester, (E)- (65 mg, 0.1 mmol) in THF (15 ml) was added lithiumaluminum hydride (1 ml, 1 M solution in THF). The resultant mixture wasstirred under nitrogen at room temperature overnight. Saturated ammoniumchloride solution (20 ml) was added and the mixture was stirred for 0.5hour. It was extracted with dichloromethane (3×50 ml) and the organicphase was dried over magnesium sulfate and evaporated. Silica gelchromatography (hexanes/ethyl acetate 4:1) gave the title compound as anoil (46 mg). ¹H-NMR (400 MHz, CDCl₃): 7.61 (s, 2 H), 7.45 (s, 2 H), 5.99(d, 1 H), 5.39 (s, 1 H), 4.84 (m, 1 H), 4.46 (m, 2 H), 1.47 (s, 6 H),1.45 (s, 18 H), 1.42

EXAMPLE 56 L-Lysine,N⁶-[[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]acetyl]

Reaction Description

To Acetic acid,[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]2,6-bis(1,1-dimethylethyl)phenoxy]-(150 mg, 0.26 mmol) in methylene chloride (1.8 mL) was added lysinemethyl ester hydrochloride (79 mg, 0.34 mmol),1-(3-dimethylaminopropyl-3-ethyl carbodiimide hydrochloride(130 mg, 0.67mmol) and dimethylaminopyridine(82 mg, 0.67 mmol). The reaction mixturewas stirred overnight and the methylene chloride evaporated. Thereaction was diluted with ether(10 mL) and washed with water (2×3 mL),dried over MgSO₄, filtered, and concentrated. The crude mixture waspurified by silica gel chromatography and elution with 50:50ether/hexane followed by 70:30 ether/hexane to give 128 mg of the methylester of product. The methyl ester was dissolved inTHF:H₂O:MeOH(2:1:1)(3 mL) and LiOH—H₂O (50 mg) was added and thereaction stirred for 1 h. The reaction was concentrated and purifiedover silica gel eluting with 20:80 methanol/hexane to give 67 mg ofproduct. 7.58 (s, 2 H), 7.44 (s, 2 H), 6.86 (m, 1 H), 5.39 (s, 1 H),4.75 (m, 1 H), 4.29 (d, J=7.2 Hz, 2 H), 3.44 (m, 2 H), 2.10 (m, 2H),1.95 (m, 2 H), 1.82 (m, 2 H), 1.46 (s, 6 H), 1.44 (s, 9 H), 1.42 (s, 9H).

EXAMPLE 57 D-Glucopyranose,6-O-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenyl]

To a suspension of β-D-Glucopyranose,6-O-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenyl]-(0.68 g) in methanol (50 ml) was added potassium carbonate (1 g) and themixture was stirred under nitrogen at room temperature overnight. It waspoured into water (200 ml), extracted with ethyl acetate (3×150 ml),washed with brine (100 ml), dried over magnesium and evaporated. Silicagel chromatography (dichloromethane/methanol 10:1 to 5:1) gave the titlecompound as an off-white solid (0.26 g). ¹H-NMR (400 MHz, CDCl₃): 7.52(s, 2 H), 7.44 (s, 2 H), 5.36 (s, 1 H), 5.31 (s) and 4.78 (br. s, 1 H),3.30-4.38 (br. m, 6 H), 1.38-1.43 (m, 42 H).

EXAMPLE 58 D-Glucitol,6-O-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenyl]

To a solution of D-Glucopyranose,6-O-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenyl]-(70 mg) in THF (5 ml) was added sodium borohydride and the mixture wasstirred under nitrogen at room temperature for 2 hours. Then saturatedammonium chloride (2 ml) was added and the mixture stirred for anotherhour. It was poured into water (50 ml) and extracted withdichloromethane (3×50 ml). The organic phase was dried over magnesiumand evaporated. Silica gel chromatography (dichloromethane/methanol100:12) gave the title compound as a white solid (19 mg). ¹H-NMR (400MHz, CDCl₃): 7.54 (s, 2 H), 7.44 (s, 2 H), 5.36 (s, 1 H), 4.35 (m, 1 H),3.30-4.10 (m, 7 H), 1.40-1.44 (m, 42 H).

EXAMPLE 59 Butanoic acid,4-[[hydroxy(2-hydroxyphenoxy)phosphinyl]oxy]-4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenylester

To a solution of Butanoic acid, 4-hydorxy-,4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenylester (60 mg, 0.1 mmol) in pyridine (1 ml) was added 1,2-phenylenephosphorochloridate (21 mg, 0.11 mmol) and the mixture was stirred undernitrogen at room temperature for 1 hour. It was evaporated and theresidue was dissolved in dichloromethane (10 ml). Water (1 ml) andacetic acid (0.5 ml) were added and the mixture was stirred for 0.5hour. It was poured into water (50 ml) and extracted withdichloromethane (2×50 ml). The organic phase was dried over magnesiumand evaporated. Silica gel chromatography (dichloromethane/methanol 5:1)gave the title compound as a white solid (21 m g). ¹H-NMR (400 MHz,CDCl₃): 7.58 (s, 2 H), 7.44 (s, 2 H), 7.15 (br. s, 1 H), 6.87 (br. s, 2H), 6.71 (br. s, 1 H), 5.37 (s, 1 H), 3.97 (br. s, 2 H), 2.48 (br. s, 2H), 1.83 (br. s, 2 H), 1.45 (s, 6 H), 1.43 (s, 18 H), 1.24 (s, 18 H).

EXAMPLE 60 Butanoic acid, 4-hydroxy-3,3-dimethyl-,4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenylester

Reaction Description

To a flask was added probucol (2.3 g, 4.46 mmol) and tetrahydrofuran (23mL). To the solution was added 60% sodium hydride in mineral oil (0.23g, 5.75 mmol), to the cloudy white mixture was added 2,2 dimethylsuccinic anhydride (1 g, 7.6 mmol). The reaction was stirred at roomtemperature for 3 h. The dark purple reaction mixture was made acidicwith 1N HCl (25 mL) and extracted twice with ethyl acetate (50 mL). Theorganic extracts were dried over MgSO₄, filtered and concentrated. Thecrude product mixture was dissolved in ether and chromatographed onsilica gel with a concentration gradient of 70:30 hexane/ether to 0:100hexane/ether. The appropriate fractions were combined and concentratedaffording 700 mg of a white solid. The white solid (214 mg, 0.332 mmol))was taken up in THF (6 mL) and borane-dimethylsulfide (2M in THF, 0.665mL, 0.664 mmol) was added and the reaction stirred for 6 h. The reactionwas quenched with concentrated HCl (0.100 mL) and the reaction stirredovernight. The reaction was diluted with ether (25 mL), washed withwater(1×5 mL), NaHCO₃ (1×5 mL), and brine (1×5 mL). The ether layer wasdried over MgSO₄, filtered, and concentrated. Radial silica gelchromatography and elution with a concentration gradient from 100:0hexane/ether to 50:50 hexane/ether gave 85 mg of product. ¹H NMR (CDCl₃,400 MHz): δ 7.64 (s, 2 H), 7.46 (s, 2 H), 5.39 (s, 1 H), 3.48 (d, J=6.8Hz, 2 H), 2.73 (s, 2 H), 1.47 (s, 6 H), 1.45 (s, 9 H), 1.35 (s, 9 H),1.11 (s, 6 H).

EXAMPLE 61 Butanoic acid, 4-(sulfoxy)-,1-[4-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenyl]ester

Reaction

Butanoic acid, 4-hydorxy-,4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenylester (12.5 g, 20.75 mmol) was dissolved in DMF (150 ml) and sulfurtrioxide trimethylamine complex (12.5 g, 87.5 mmol) was added. Themixture was stirred at room temperature overnight. It was evaporated andthe residue was dissolved in dichloromethane (100 ml), washed with water(2×50 ml). The aqueous phase was extracted with dichloromethane (75 ml).The combined organic phase was dried over magnesium sulfate andevaporated. Silica gel chromatography (dichloromethane/methanol 10:1,5:1) gave a residue which was used for the next step of reaction.

The above product was dissolved in THF (200 ml). NaOH (0.8 g, 20 mmol)in water (5 ml) was added. The mixture was stirred at room temperaturefor 2 h and then evaporated. 1 N NaOH solution (200 ml) was added to theresidue and stirred for 0.5 h. It was filtered and a yellowish solid wascollected, which was dried to a constant weight (9.23 g).

The present invention also includes the use of compounds of the formulas(I) and (II) in inhibiting the peroxidation of LDL lipid and ininhibiting the progression of atherosclerosis in patients in needthereof.

As used herein, the term “patient” refers to warm-blooded animals ormammals, and in particular humans, who are in need of the therapydescribed herein.

The following examples illustrate the use of compounds of formula (I)according to the present invention. These examples are illustrative onlyand are not intended to limit the scope of the invention in any way.

EXAMPLE 62 Lipid Screen & IC₅₀ Determination Protocol

Preparation of HEPG2

HEPG2 cell was started in 10 ml of MEM, 10% FBS, 1 mM Sodium Pyruvate.The cells were incubated in a tissue culture incubator. The cells weresplit into 4×96-wells plate in MEM, 10% FBS, 1 mM Sodium Pyruvate andallowed to grow to about 50% confluency and then removed.

Day 1 Treatment:

The cells were treated with the desired concentration of compounds in100 μl DMEM, 1% RSA for 24 hours. The compounds are dissolved in DMSO.For IC₅₀, the range of concentration is 10 uM-40 uM, with eachconcentration being done in triples.

On the same day, 4×96-wells NuncImmunoSorb plate is coated with 100 μlof mouse anti-human ApoB monoclonal 1D1 (1:1000 dilution in 1×PBS, pH7.4). The coating is allowed overnight.

Day 2 ApoB ELISA:

The coated plate is washed 3 times with 1×PBS, pH 7.4, −0.05% Tween 20.100 μl of the standards is added to the selected wells. ApoB standardsare prepared at 6.25, 3.12, 1.56, 0.78, 0.39 ng, and each concentrationis done in triplicates.

For samples:

90 μl of 1×PBS, pH 7.4, −0.05% Tween 20 is added to each wellcorresponding to the sample. 10 μl of media is transferred from thetreated HEPG2 plates to the ApoB ELISA plate. The plate is incubated atroom temperature for 2 hours, rocking gently.

Wash the coated plate 3× with 1×PBS, pH 7.4, −0.05% Tween 20. Add 100 μlof sheep anti-human ApoB polyclonal from Boehringer Mannheim. (1:2000dilution in 1×PBS, pH 7.4, −0.05% Tween 20) from Boehringer Mannheim.Incubate at room temperature for 1 hour, rocking gently. Wash the coatedplate 3× with 1×PBS, pH 7.4, −0.05% Tween 20. Add 100 μl of rabbitanti-sheep IgG (1:2000 dilution in 1×PBS, pH 7.4, −0.05% Tween 20).Incubate at room temperature for 1 hour, rocking gently. Wash the coatedplate 3× with 1×PBS, pH 7.4, −0.05% Tween 20. Add 100 μl of substrate(10 ml of distilled water, 100 μl of TMB (10 mg/ml), and 1 μl ofhydrogen peroxide). Allow color to emerge and stop reaction with 25 ulof 8N sulfuric acid. Wells are read with MicroPlate Reader@450 nM. Graphaccumulation of ApoB in media as a percentage of control for each sampleand their concentration. A determination of IC₅₀ is obtained from thegraph.

EXAMPLE 63 VCAM-1 Assay

Splitting the Cells

Two to four confluent P150 plates are trypsinized and the cellstransferred to a 50 mL conical centrifuge tube. The cells are pelleted,resuspended, and counted using thetrypan blue exclusion method.

Cells are resuspended at a concentration of 36,000 cells/mL and 1 mL isaliquoted per well.

Cells are split into 24 well tissue culture plates. The cells in eachwell should be approximately 90-95% confluent by the following day.Cells should not be older than passage 8.

Preparation of Compounds

Water soluble compounds

Compounds are initially screened at 50 μM and 10 μM. A 50 mM stocksolution for each compound is prepared in culture medium. The stocksolution is diluted to 5 mM and 1 mM. When 10 μL of the 5 mM solution isadded to the well (1 mL medium/well), the final concentration will be 50μM. Adding 10 μL of the 1 mM solution to the well will give a finalconcentration of 10 μM.

Water insoluble compounds

Compounds which will not go into solution in culture medium areresuspended in DMSO at a concentration of 25 mM. The stock solution isthen diluted to the final concentration in culture medium. The oldmedium is aspirated and 1 mL of the new medium with the compound isadded. For example, if the final concentration is 50 μM, the 2 μL of the25 mM stock is added per mL of culture medium. The 50 mM solution isdiluted for lower concentrations.

Adding the compounds

The compounds are added to the plate (each compound is done induplicate). One plate is done for VCAM expression and one plate is donefor ICAM expression.

Immediately after the compounds are added, TNF is added to each well.100 units/mL TNF is usually added to each well. Since each lot of TNFvaries in the number of units, each new lot is titrated to determine theoptimum concentration. Therefore this concentration will change. If 100units/mL is bing used, dilute the TNF to 10 units/μL and add 10 μL toeach well.

The plates are incubated at 37° C., 5% CO₂ overnight (approximately 16hours). The next day the plates are checked under the microscope to seeif there are any visual signs of toxicity. Records are made of any celldeath, debris, or morphology changes, as well as insoluble compounds(particulate or turbity).

EXAMPLE 64 ELISA Assay

In order to assess MCP-1, the media (500 μL) is saved and frozen at −70°C. Wash cells once with roughly 1 ml/well of Hanks Balance Salt Solution(HBSS) or PBS. Gently empty the wash solution and then tap the plateonto paper towels. Add either 250 μL/well of HBSS+5% FCCS to the plank(no primary antibody wells) or 250 μL/well of primary antibody dilutedin HBSS+5% FCS. Incubate the 30 minutes at 37° C. Wash the wells twicewith 0.5 mL/well HBSS or PBS and gently tap the plates onto paper towelsafter the last wash. Add 250 μL/well of HRP-conjugated second antibodydiluted in HBSS+5% FCS to every well including the blank wells (noprimary antibody). Incubate at 37° C. for 30 minutes. Wash the wellsfour times with 0.5 mL/well HBSS or PBS and gently tap the plates ontopaper towels after the last wash. Add 250 μL/well of substrate solution.Incubate at room temperature in the dark until there is adequate colordevelopment (blue). Note the length of time incubation was performed(typically 15-30 minutes). Add 75 μL/well stopper solution (8N sulfuricacid), and read A450 nm.

Antibodies and solutions

1. Substrate solution is made immediately prior to use and contains:

water 10 mL 30% hydrogen peroxide 1 μL TMB(3,3′,5,5′-tetramethylbenzidine) 100 μL

TMB stock solution: To 10 mg TMB, add 1 mL acetone. Store at 4° C.protected from light.

2. VCAM-1 Ab: stock .1 μg/μL final concentration 0.25 μg/mL

mix 25 μL stock VCAM-1 (Southern Biotechnology) and 10 mL HBSS+5% FCS

3. ICAM-1 Ab: stock .1 μg/μL final concentration 0.25 μg/mL

mix 25 μL stock ICAM-1 (Southern Biotechnology) and 10 mL HBSS+5% FCS

4. Secondary Ab: HRP-conjugated goat antimouse IgG diluted 1:500

mix 20 μL stock (Southern Biotechnology) and 10 mL HBSS+5% FCS

The degree of inhibition of the compounds of formulas (I) and (II) wasdetermined by the assays described in Examples 62-64. The results areprovided in Table 1.

TABLE 1 ApoB/ VCAM-1 IC₅₀ HepG2 ID₅₀ or % inhibition or % inhibitionCompound at [μM] LD₅₀ at [μM] 2,6-di-tert-butyl-4- 80 200  7% at 15thio(4′(methyl)phenyl- acetic acid))phenol 2,6-di-tert-butyl-4- 10 20027 thio(4′- nitrobenzyl)phenol 2,6-di-tert-butyl-4- 15 0.4 NE thio(4′-nitrophenethyl)phenol 2,6-di-tert-butyl-4- 75 200 NE thio(butanoicacid)phenol 2,6-di-tert-butyl-4- 6 50 NE thio(3′,5′-ditert-butyl,4′-hydroxy butanedioic acid ester)phenol 2,6-di-tert-butyl-4- NE >100 NEthio(4′(methyl)benzoic acid)phenol 2,6-di-tert-butyl-4- 50 NEthio(2′-acetoxy,2′- methylpropyl)phenol 2,6-di-tert-butyl-4- 13 200 20thio(3′- nitrobenzyl)phenol 2,6-di-tert-butyl-4- 8 400 32 thio(2′,4′-dinitrobenzyl)phenol (2,6-di-tert-butyl-4- 5 300 16 thio(4′-(trifluoromethyl)benzyl) phenol 2,6-di-tert-butyl-4- 40 400 NEthio((2′-furancarboxylic acid)-5-methyl)phenol 2,6-di-tert-butyl-4- 20350 31 thio(4′-methyl-N,N- di-methylbenzenesulfona- mide)phenol2,6-di-tert-butyl-4- 50 <100 NE sulfinyl(4′- nitrobenzyl)phenol2,6-di-tert-butyl-4- 40 100 25 (sulfonyl-(4′- nitrobenzyl))phenol2,6-di-tert-butyl-4- 18 75 40 thio(4′- acetoxybenzyl)phenol2,6-di-tert-butyl-4- 75 22 thio(4′- methylbenzyl)phenol2,6-di-tert-butyl-4- 35 30 thio(4′- fluorobenzyl)phenol2,6-di-tert-butyl-4- 25% at 50 thio(3′-propanesulfonic acid)phenol2,6-di-tert-butyl-4- 10 19 thio(5′-methyl-2′- ((dimethylamino)methyl)furan)phenol 2,6-di-tert-butyl-4- 30% at 50 100 thio(3′-(dimethylamino)propyl)) phenol 2,6-di-tert-butyl-4- 40% at 50 100 30thio((1′- (acetoxy))pentyl)phenol 2,6-di-tert-butyl-1- NE <10 methoxy-4-thio(4′- trifluoromethyl)benzyl) benxene 2,6-di-tert-butyl-4-15 50 53% at 15 thio(4′- (methyl)phenylethyl alcohol))phenolPhenol,4-[[1-[3,5- 30% at 50 >100 17% at 15 bis(1,1-dimethylethyl)4-[(4-nitrophenyl) methoxy] phenyl]thio]-1- methylethyl]thio]2,6-bis(1,1-dimethylethyl)- Butanedioic acid, mono 5.6 23 65% at 15[4-[[1-[[3,5-bis(1,1- dimethylethyl)-4- hydroxyphenyl]thio]-1-methylethyl]thio]2,6- bis(1,1- dimethylethyl)phenyl] ester2-Furancarboxylic acid, 25 400 17% at 15 5-nitro-,4-[[1-[[3,5-bis(1,1-dimethylethyl)- 4-hydroxyphenyl]thio]- 1-methylethyl]thio]-2,6-bis(1,1- dimethylethyl)phenyl ester Butanoic acid, 4-[4-[[1- 19 75 41%at 15 [[3,5-bis(1,1- dimethylethyl)-4- hydroxyphenyl]thio]-1-methylethyl]thio]2,6- dimethylphenoxy]- Phenol, 4-[[1-[[4-(4- 8 25aminobutoxy)-3,5- bis(1,1- dimethylethyl) phenyl]thio]-1-methylethyl]thio]2,6- bis(1,1-dimethylethyl)- Phenol, 4-[[1-[[4-(4- 9 25aminobutoxy)-3,5- bis(1,1- dimethylethyl) phenyl]thio]-1-methylethyl]thio]2,6- bis(1,1-dimethylethyl)- Butanoic acid, 4- 6 25081% at 15 hydroxy-, 4-[[1-[[3,5- bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]- 1-methylethyl]thio]-2,6- bis(1,1-dimethylethyl)phenyl ester Propanoic acid, 2,2- 25% at 25 dimethyl-,[4-[[1-[[3,5- bis(1,1-dimethylethyl)-4- hydroxyphenyl]thio]-1-methylethyl]thio]-2,6- bis(1,1- dimethylethyl)phenoxy] methyl esterPhenol, 4-[[1-[[4-(4- 5 12.5 aminobutoxy)phenyl]thio]-1-methylethyl]thio]- 2,6-bis(1,1- dimethylethyl)- Butanoic acid,4-[4-[[1- 19 >100 47% at 15 [[3,5-bis(1,1- dimethylethyl)-4-hydroxyphenyl]thio]-1- methylethyl]thio] phenoxy]- Acetic acid,[4-[[1-[[3,5- 10 50 NE bis(1,1-dimethylethyl)- 4-hydroxyphenyl]thio]-1-methylethyl]thio]2,6- bis(1,1- dimethylethyl)phenoxy]- Butanoic acid,4-amino- 8 25 4-oxo-,4-[[1-[[3,5- bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]- 1-methylethyl]thio]-2,6- bis(1,1-dimethylethyl)phenyl ester Glycine, 4-[[1-[[3,5- 10% at 20 35bis(1,1-dimethylethyl)- 4-hydroxyphenyl]thio]- 1-methylethyl]thio]-2,6-dimethylphenyl ester Butanedioic acid, 8 20 mono[4-[[1-[[3,5-bis(1,1-dimethylethyl)- 4-hydroxyphenyl]thio)- 1-methylethyl}-2,6-dimethylphenyl] ester Butanedioic acid, 40% at 100 mono[4-[[1-[[3,5-bis(1,1-dimethylethyl)- 4-hydroxyphenyl]thio)- 1-methylethyl}thio-2,6-bis(1,1- dimethylethyl)phenyl methyl ester Glycine, 4-[[1-[[3,5- 5 2530% at 5  bis(1,1-dimethylethyl)-4- hydroxyphenyl]thio]-1-methylethyl]thio]-2,6- bis(1,1- dimethylethyl)phenyl ester Pentanedioicacid, (1- NE 25 methylethylidene)bis(thio {2,6-bis(1,1-dimethylethyl)-4,1- phenylene)] ester Pentanedioic acid, 8.7 25 70% at15 mono[4-[[1-[[3,5- bis(1,1-dimethylethyl)-4- hydroxyphenyl]thio]-1-methylethyl]thio]-2,6- bis(1,1- dimethylethyl)phenyl] ester Butanoicacid, 4-[4-[[1- 11 25 77% at 15 [[3,5-bis(1,1- dimethylethyl)-4-hydroxyphenyl]thio]-1- methylethyl]thio]-2,6- bis(1,1-dimethylethyl)phenoxy]- Butanedioic acid, (1- NE 25methylethylidine)bis[thio [2,6-bi(1,1- dimethylethyl)-4,1- phenylene}}ester, Glycine, (1- NE methylethylidene)bis [bis[thio2,6-bis(1,1-dimethylthyl)-4,1- phenylene]] ester, dihydrochloride Oxiranemethanol,α-[[4- 45 [[1-[[3,5-bis(1,1- dimethylethyl)-4- hydroxyphenyl]thio]-1-methylethyl]thio]-2,6- bis(1,1- dimethylethyl)phenoxy] methyl]-;Oxiranemethanol, 3-[[4- >100 NE [[1-[[3,5-bis(1,1- dimethylethyl)-4-hydroxyphenyl]thio]-1- methylethyl]thio]-2,6- bis(1,1-dimethylethyl)phenoxy] methyl]-; Oxiranemethanol, α- 60[[[3-[[4-[[1-[[3,5- bis(1,1-dimethylethyl)-4- hydroxyphenyl]thio]-1-methylethyl]thio]-2,6- bis(1,1- dimethylethyl)phenoxy]methyl]oxiranyl]methoxy] methyl]- Phenol, 4-[[1-[[3,5- NE at 50bis(1,1-dimethylethyl)-4- (oxiranylmethoxy)phenyl] thio]-1-methylethyl]thio]-2,6- bis(1,1-dimethylethyl)- Glycine, N-[3-[4-[[1- 1650 45% at 15 [[3,5-bis(1,1- dimethylethyl)-4- hydroxyphenyl]thio]-1-methylethyl]thio]-2,6- bis(1,1- dimethylethyl)phenoxy] 2-hydroxypropyl]-1,2,3-Butanetriol, 4-[4- 6 20  6% at 1  [[1-[[3,5-bis(1,1-dimethylethyl)-4- hydroxyphenyl]thio]-1- methylethyl]thio]-2,6- bis(1,1-dimethylethyl)phenoxy]- 2-hydroxypropyl]- Phenol, 4-[[1-[[3,5- 75bis(1,1-dimethylethyl)-4- (3-ethoxy-2- hydroxypropoxy)phenyl] thio]-1-methylethyl]thio]-2,6- bis(1,1-dimethylethyl)-; 1,2-Propanediol, 3-[4-30 40% at 15 [[1-[[3,5-bis(1,1- dimethylethyl)-4- hydroxyphenyl]thio]-1-methylethyl]thio]-2,6- bis(1,1- dimethylethyl)phenoxy]- Phenol,4-[[1-[[3,5- NE at 50 bis(1,1-dimethylethyl)-4- ethoxyphenyl]thio]-1-methylethyl]thio]-2,6- bis(1,1-dimethylethyl)- 2-Propenoic acid, 3-[4-NE at 50 [[1-[[3,5-bis(1,1- dimethylethyl)-4- hydroxyphenyl]thio]-1-methylethyl[thio]-2,6- bis(1,1- dimethylethyl)phenoxy]-, ethyl ester,(E)- Butanedioic acid, NE 89% at 15 mono[4[[1-[[3,5-bis(1,1-dimethylethyl)-4- methoxyphenyl]thio]1- methylethyl]thio]-2,6-bis(1,1- dimethylethyl)phenyl] ester Phenol, 4-[[1-[[4-[2-[4- 55(dimethylamino)phenyl] ethoxy]-3,5-bis(1,1- dimethylethyl)phenyl]thio]-1-methylethyl]thio]- 2,6-bis(1,1- dimethylethyl)- Benzenamine, 4,4′-[(1-NE methylethylidene)bis[thio [2,6-bis(1,1- dimethylethyl)-4,1-phenylene]oxy-2,1- ethanediyl]]bis [N,N- dimethyl- L-Arginine,mono[4-[[1- 15 50 93% at 15 [[3,5-bis(1,1- dimethylethyl)-4-hydroxyphenyl]thio]-1- methylethyl]thio]-2,6- bis(1,1-dimethylethyl)phenyl butanedioate] pentanedioic acid, 4-[[1- 80 NE[[3,5-bis(1,1- dimethylethyl)-4- hydroxyphenyl]thio]-1-methylethyl]thio]-,6- bis(1,1- dimethylethyl)phenyl methyl ester2-Propenoic acid, 3-[4- 30 NE [[1-[[3,5-bis(1,1- dimethylethyl)-4-hydroxyphenyl]thio]-1- methylethyl]thio]-2,6- bis(1,1- dimethylethyl)phenoxy]-, (E)- α-D-Galactopyranose, 6- 45 O-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4- hydroxyphenyl)thio]-1- methylethyl]thio]-2,6- bis(1,1-dimethylethyl)phenyl]- 1,2:3,4-bis-O-(1- methylethylidene) Phenol,4-[[1-[[4-[3- 22% at 50 (dimethylamino)propoxy]- 3,5-bis(1,1-dimethylethyl)phenyl]thio]- 1-methylethyl]thio]- 2,6-bis(1,1-dimethylethyl)- Glycine, N-[[4-[[1-[[3,5- 15 50 83% at 15bis(1,1-dimethylethyl)- 4-hydroxyphenyl]thio]-1, methylethyl]thio]-2,6-bis(1,1- dimethylethyl)phenoxy] acetyl]- Glutamic acid, N-[[4- 75 10094% at 15 [[1-[[3,5-bis(1,1- dimethylethyl)-4- hydroxyphenyl]thio]-1-methylethyl]thio]-2,6- bis(1,1- dimethylethyl)phenoxy] acetyl]-L-Glutamic acid, N-[3- 10 50 [4-[[1-[[3,5-bis(1,1- dimethylethyl-4-hydroxyphenyl]thio]-1- methylethyl]thio]-2,6- bis(1,1-dimethylethyl)phenoxy]- 2-hydroxypropyl]-di-, diethyl ester Glycine,N-[4-[4-[[1- 50 >100 [[3,5-bis(1,1- dimethylethyl)-4-hydroxphenyl]thio]-1- methylethyl]thio]-2,6-bis (1,1-dimethylethyl)phenoxy]- 2,3-dihydroxybutyl]- L-Lysine, N⁶-[3-[4[[1- 75100 [[3,5-bis(1,1- dimethylethyl)-4- hydroxyphenyl]thio]-1-methylethy]thio]-2, 6-bis(1,1- dimethylethyl)phenoxy]- 2-hydroxypropyl]-2-Propenoic acid, 4-[4- 75 [[1-[[3,5-bis(1,1- dimethylethyl)-4-hydroxyphenyl]thio]-1- methylethyl]thio]-2,6- bis(1,1-dimethylethyl)phenoxy] butyl ester Phenol, 4-[[1-[[3,5- 125bis(1,1-dimethylethyl)-4- hydoxybutoxy)phenyl] thio]-1-methylethyl]thio]-2,6- bis(1,1-dimethylethyl)- β-D-Glucopyranose, 6- 30%at 50 O-[4-[[1-[[3,5-bis(1,1- dimethylethyl)-4- hydroxyphenyl]thio]-1-methylethyl]thio]-2,6- bis(1,1- dimethylethyl)phenyl]- 1-H-Tetrazole-1-25% at 50 butanoic acid, 4[[1- [[3,5-bis(1,1- dimethylethyl)-4-hydroxyphenyl]thio]-1- methylethyl]thio]-2,6- bis(1,1-dimethylethyl)phenyl ester Phenol, 4-[[1-[[3,5- 55bis(1,1-dimethylethyl)-4- [[3-hydroxy-1- propenyl)oxy]phenyl] thio]-1-methylethyl]thio]- 2,6-bis(1,1- dimethylethyl)- L-Lysine, N⁶-[[4-[[1-30% at 50 NE [[3,5-bis(1,1- dimethylethyl)-4- hydroxyphenyl]thio]-1-methylethyl]thio]-2,6- bis(1,1- dimethylethyl)phenoxy] acetyl]-D-Glucopyranose, 6-O- 10 50 [4-[[1-[[3,5-bis(1,1- dimethylethyl)-4-hydroxyphenyl]thio]-1- methylethyl]thio]-2,6- bis(1,1-dimethylethyl)phenyl]- D-Glucitol, 6-O-[4-[[1- 15 50 [[3,5-bis(1,1-dimethylethyl)-4- hydroxyphenyl]thio]-1- methylethyl]thio]-2,6- bis(1,1-dimethylethyl)phenyl]- Butanoic acid, 4- 43 75 [[hydroxy(2-hydroxyphenoxy) phosphinyl] oxy]-4-[[1-[[3,5- bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1- methylethyl]thio]-2,6- bis(1,1-dimethylethyl)phenyl ester Butanoic acid, 4- 110 90% at 15hydroxy-3,3-dimethyl-, 4-[[1-[[3,5-bis(1,1- dimethylethyl)-4-hydroxyphenyl]thio]-1- methylethyl]thio]-2,6- bis(1,1-dimethylethyl)phenyl ester Butanoic acid, 4- 20 50 NE (sulfoxy)-,1-[4-[[3,5- bis(1,1-dimethylethyl)- 4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6- bis(1,1- dimethylethyl)phenyl]ester

Pharmaceutical Compositions

Mammals, and specifically humans, suffering from any of theabove-described conditions can be treated by the topical, systemic ortransdermal administration of a composition comprising an effectiveamount of the compound of formula (I) or formula (II) or apharmaceutically acceptable salt thereof, optionally in apharmaceutically acceptable carrier or diluent.

The composition is administered subcutaneously, intravenously,intraperitoneally, intramuscularly, parenterally, orally, submucosally,by inhalation, transdermally via a slow release patch, or topically, inan effective dosage range to treat the target condition. An effectivedose can be readily determined by the use of conventional techniques andby observing results obtained under analogous circumstances. Indetermining the effective dose, a number of factors are consideredincluding, but not limited to: the species of patient; its size, age,and general health; the specific disease involved; the degree ofinvolvement or the severity of the disease; the response of theindividual patient; the particular compound administered; the mode ofadministration; the bioavailability characteristics of the preparationadministered; the dose regimen selected; and the use of concomitantmedication. Typical systemic dosages for all of the herein describedconditions are those ranging from 0.1 mg/kg to 500 mg/kg of body weightper day as a single daily dose or divided daily doses. Preferred dosagesfor the described conditions range from 5-1500 mg per day. A moreparticularly preferred dosage for the desired conditions ranges from25-750 mg per day. Typical dosages for topical application are thoseranging from 0.001 to 100% by weight of the active compound.

The compound is administered for a sufficient time period to alleviatethe undesired symptoms and the clinical signs associated with thecondition being treated.

The active compound is included in the pharmaceutically acceptablecarrier or diluent in an amount sufficient to deliver to a patient atherapeutic amount of compound in vivo in the absence of serious toxiceffects.

The concentration of active compound in the drug composition will dependon absorption, inactivation, and excretion rates of the drug as well asother factors known to those of skill in the art. It is to be noted thatdosage values will also vary with the severity of the condition to bealleviated. It is to be further understood that for any particularsubject, specific dosage regimens should be adjusted over time accordingto the individual need and the professional judgment of the personadministering or supervising the administration of the compositions, andthat the dosage ranges set forth herein are exemplary only and are notintended to limit the scope or practice of the claimed composition. Theactive ingredient may be administered at once, or may be divided into anumber of smaller doses to be administered at varying intervals of time.

A preferred mode of administration of the active compound for systemicdelivery is oral. Oral compositions will generally include an inertdiluent or an edible carrier. They may be enclosed in gelatin capsulesor compressed into tablets. For the purpose of oral therapeuticadministration, the active compound can be incorporated with excipientsand used in the form of tablets, troches, or capsules. Pharmaceuticallycompatible binding agents, and/or adjuvant materials can be included aspart of the composition.

The tablets, pills, capsules, troches and the like can contain any ofthe following ingredients, or compounds of a similar nature: a bindersuch as microcrystalline cellulose, gum tragacanth or gelatin; anexcipient such as starch or lactose, a disintegrating agent such asalginic acid, Primogel, or corn starch; a lubricant such as magnesiumstearate or Sterotes; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring.

When the dosage unit form is a capsule, it can contain, in addition tomaterial of the above type, a liquid carrier such as a fatty oil. Inaddition, dosage unit forms can contain various other materials whichmodify the physical form of the dosage unit, for example, coatings ofsugar, shellac, or other enteric agents.

The compound or its salts can be administered as a component of anelixir, suspension, syrup, wafer, chewing gum or the like. A syrup maycontain, in addition to the active compounds, sucrose as a sweeteningagent and certain preservatives, dyes and colorings and flavors.

The compound can also be mixed with other active materials which do notimpair the desired action, or with materials that supplement the desiredaction. The active compounds can be administered in conjunction withother medications used in the treatment of cardiovascular disease,including lipid lowering agents such as probucol and nicotinic acid;platelet aggregation inhibitors such as aspirin; antithrombotic agentssuch as coumadin; calcium channel blockers such as varapamil, diltiazem,and nifedipine; angiotensin converting enzyme (ACE) inhibitors such ascaptopril and enalopril, and β-blockers such as propanalol, terbutalol,and labetalol. The compounds can also be administered in combinationwith nonsteroidal antiinflammatories such as ibuprofen, indomethacin,fenoprofen, mefenamic acid, flufenamic acid, sulindac. The compound canalso be administered with corticosteriods.

Solutions or suspensions used for parenteral, intradermal, subcutaneous,or topical application can include the following components: a sterilediluent such as water for injection, saline solution, fixed oils,polyethylene glycols, glycerine, propylene glycol or other syntheticsolvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. pH can be adjusted withacids or bases, such as hydrochloric acid or sodium hydroxide. Theparenteral preparation can be enclosed in ampoules, disposable syringesor multiple dose vials made of glass or plastic.

If administered intravenously, preferred carriers are physiologicalsaline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) orphosphate buffered saline (PBS).

In a preferred embodiment, the active compounds are prepared withcarriers that will protect the compound against rapid elimination fromthe body, such as a controlled release formulation, including implantsand microencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid.Methods for preparation of such formulations will be apparent to thoseskilled in the art. The materials can also be obtained commercially fromAlza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions(including liposomes targeted to infected cells with monoclonalantibodies to viral antigens) are also preferred as pharmaceuticallyacceptable carriers. These may be prepared according to methods known tothose skilled in the art, for example, as described in U.S. Pat. No.4,522,811 (which is incorporated herein by reference in its entirety).For example, liposome formulations may be prepared by dissolvingappropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine,stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, andcholesterol) in an inorganic solvent that is then evaporated, leavingbehind a thin film of dried lipid on the surface of the container. Anaqueous solution of the compound is then introduced into the container.The container is then swirled by hand to free lipid material from thesides of the container and to disperse lipid aggregates, thereby formingthe liposomal suspension.

Suitable vehicles or carriers for topical application can be prepared byconventional techniques, such as lotions, suspensions, ointments,creams, gels, tinctures, sprays, powders, pastes, slow-releasetransdermal patches, suppositories for application to rectal, vaginal,nasal or oral mucosa. In addition to the other materials listed abovefor systemic administration, thickening 0agents, emollients, andstabilizers can be used to prepare topical compositions. Examples ofthickening agents include petrolatum, beeswax, xanthan gum, orpolyethylene, humectants such as sorbitol, emollients such as mineraloil, lanolin and its derivatives, or squalene.

Modifications and variations of the present invention relating tocompounds that inhibit the suppression of VCAM-1 and methods of treatingdiseases mediated by the expression of VCAM-1 will be obvious to thoseskilled in the art from the foregoing detailed description of theinvention. Such modifications and variations are intended to come withthe scope of the appended claims.

We claim:
 1. A compound of the formula

or a pharmaceutically acceptable salt or ester thereof.
 2. A compound ofthe formula

or a pharmaceutically acceptable salt thereof.
 3. A pharmaceuticalcomposition comprising a compound of the formula

or a pharmaceutically acceptable salt thereof, together with apharmaceutically acceptable carrier.
 4. The pharmaceutical compositionof claim 3, wherein the pharmaceutically acceptable carrier is suitablefor oral administration.
 5. The pharmaceutical composition of claim 3,wherein the pharmaceutically acceptable carrier is suitable for topicaladministration.
 6. The pharmaceutical composition of claim 3, whereinthe pharmaceutically acceptable carrier is suitable for intravenousadministration.
 7. The pharmaceutical composition of claim 3, whereinthe pharmaceutically acceptable carrier is suitable for subcutaneousadministration.
 8. The pharmaceutical composition of claim 3, whereinthe pharmaceutically acceptable carrier is suitable for intraperitonealadministration.
 9. The pharmaceutical composition of claim 3, whereinthe pharmaceutically acceptable carrier is suitable for intramuscularadministration.
 10. The pharmaceutical composition of claim 3, whereinthe pharmaceutically acceptable carrier is suitable for submucosaladministration.
 11. The pharmaceutical composition of claim 3, whereinthe pharmaceutically acceptable carrier is suitable for inhalationadministration.
 12. The pharmaceutical composition of claim 3, whereinthe pharmaceutically acceptable carrier is suitable for transdermaladministration.
 13. A method for the treatment of an inflammatorydisorder, comprising administering to a host in need thereof aneffective treatment amount of a compound of the formula

or a pharmaceutically acceptable salt thereof.
 14. The method of claim13, wherein the inflammatory disorder is arthritis.
 15. The method ofclaim 13, wherein the inflammatory disorder is rheumatoid arthritis. 16.The method of claim 13, wherein the inflammatory disorder isosteoarthritis.
 17. The method of claim 13, wherein the inflammatorydisorder is asthma.
 18. The method of claim 13, wherein the inflammatorydisorder is dermatitis.
 19. The method of claim 13, wherein theinflammatory disorder is multiple sclerosis.
 20. The method of claim 13,wherein the inflammatory disorder is psoriasis.
 21. A method for thetreatment of a disorder mediated by VCAM-1, comprising administering toa host in need thereof an effective treatment amount of a compound ofthe formula

or a pharmaceutically acceptable salt thereof.
 22. A method for thetreatment of a cardiovascular disorder, comprising administering to ahost in need thereof an effective treatment amount of a compound of theformula

or a pharmaceutically acceptable salt thereof.
 23. The method of claim22, wherein the cardiovascular disorder is selected from the groupconsisting of atherosclerosis, post-angioplasty restenosis, coronaryartery disease, angina and small artery disease.
 24. A method for thesuppressing the expression of a redox-sensitive gene or activating agene that is suppressed through a redox-sensitive pathway, comprisingadministering to a host in need thereof an effective treatment amount ofa compound of the formula

or a pharmaceutically acceptable salt thereof.
 25. The method of claim24, wherein the redox-sensitive gene expresses cytokines.
 26. A methodof treating an immune response, comprising administering to a host inneed thereof an effective treatment amount of a compound of the formula

or a pharmaceutically acceptable salt thereof.